Anti-fungal peptides

ABSTRACT

The present invention relates generally to anti-fungal peptides derived from or based on Domain III (amino acids 142-169) of bactericidal/permeability-increasing protein (BPI) and in vivo or in vitro uses of such peptides.

This is a continuation of U.S. application Ser. No. 08/621,259, filedMar. 21, 1996, now U.S. Pat. No. 5,858,974, This is acontinuation-in-part of U.S. patent application Ser. No. 08/504,841filed Jul. 20, 1995 now abandoned, which is a continuation-in-part ofU.S. patent application Ser. No. 08/372,105 filed Jan. 13, 1995 now U.S.Pat. No. 5,627,153, which is a continuation-in-part of U.S. patentapplication Ser. No. 08/306,473 filed Sep. 15, 1994 now U.S. Pat. No.5,652,332 and also a continuation-in-part of U.S. patent applicationSer. No. 08/273,540 filed Jul. 11, 1994 now abandoned, each of which isa continuation-in-part of U.S. patent application Ser. No. 08/209,762filed Mar. 11, 1994 now U.S. Pat. No. 5,733,872 , which is acontinuation-in-part of U.S. patent application Ser. No. 08/183,222filed Jan. 14, 1994, which is a continuation-in-part of U.S. patentapplication Ser. No. 08/093,202 filed Jul. 15, 1993 now abandoned whichis a continuation-in-part of U.S. patent application Ser. No. 08/030,644filed Mar. 12, 1993 now U.S. Pat. No. 5,348,942, all of which are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to anti-fungal peptides derivedfrom or based on Domain III (amino acids 142-169) ofbactericidal/permeability-increasing protein (BPI) and therapeutic usesof such peptides.

BPI is a protein isolated from the granules of mammalianpolymorphonuclear leukocytes (PMNs or neutrophils), which are bloodcells essential in the defense against invading microorganisms. HumanBPI protein has been isolated from PMNs by acid extraction combined witheither ion exchange chromatography [Esbach, J. Biol. Chem., 254:11000(1979)] or E. coli affinity chromatography [Weiss, et al., Blood, 69:652(1987)]. BPI obtained in such a manner is referred to herein as naturalBPI and has been shown to have potent bactericidal activity against abroad spectrum of gram-negative bacteria. The molecular weight of humanBPI is approximately 55,000 daltons (55 kD). The amino acid sequence ofthe entire human BPI protein and the nucleic acid sequence of DNAencoding the protein have been reported in FIG. 1 of Gray et al., J.Biol. Chem., 264:9505 (1989), incorporated herein by reference. The Grayet al. DNA and amino acid sequences are set out in SEQ ID NOS: 251 and252 hereto.

BPI is a strongly cationic protein. The N-terminal half of BPI accountsfor the high net positive charge; the C-terminal half of the moleculehas a net charge of -3. [Elsbach and Weiss (1981), supra.] A proteolyticN-terminal fragment of BPI having a molecular weight of about 25 kD hasan amphipathic character, containing alternating hydrophobic andhydrophilic regions. This N-terminal fragment of human BPI possesses theanti-bacterial efficacy of the naturally-derived 55 kD human BPIholoprotein. [Ooi et al., J. Bio. Chem., 262: 14891-14894 (1987)]. Incontrast to the N-terminal portion, the C-terminal region of theisolated human BPI protein displays only slightly detectableanti-bacterial activity against gram-negative organisms. [Ooi et al., J.Exp. Med., 174:649 (1991).) An N-terminal BPI fragment of approximately23 kD, referred to as "rBPI2," has been produced by recombinant meansand also retains anti-bacterial activity against gram-negative organisms[Gazzano-Santoro et al., Infect. Immun. 60:47544761 (1992)]. In thatpublication, an expression vector was used as a source of DNA encoding arecombinant expression product (rBPI₂₃). The vector was constructed toencode the 31-residue signal sequence and the first 199 amino acids ofthe N-terminus of the mature human BPI, as set out in SEQ ID NOS: 251and 252 taken from Gray et al., supra, except that valine at position151 is specified by GTG rather than GTC and residue 185 is glutamic acid(specified by GAG) rather than lysine (specified by AAG). Recombinantholoprotein, also referred to as rBPI, has also been produced having thesequence set out in SEQ ID NOS: 251 and 252 taken from Gray et al.,supra, with the exceptions noted for rBPI₂₃. An N-terminal fragmentanalog designated rBPI₂₁ or rBPI₂₁ Δcys has been described in co-owned,copending U.S. Pat. No. 5,420,019 which is incorporated herein byreference. This analog comprises the first 193 amino acids of BPIholoprotein as set out in SEQ ID NOS: 251 and 252 but wherein thecysteine at residue number 132 is substituted with alanine, and with theexceptions noted for rBPI₂₃.

The bactericidal effect of BPI has been reported to be highly specificto gram-negative species, e.g., in Elsbach and Weiss, Inflammation:Basic Principles and Clinical Correlates, eds. Gallin et al., Chapter30, Raven Press, Ltd. (1992). BPI is commonly thought to be non-toxicfor other microorganisms, including yeast, and for higher eukaryoticcells. Elsbach and Weiss (1992), supra, reported that BPI exhibitsanti-bacterial activity towards a broad range of gram-negative bacteriaat concentrations as low as 10⁻⁸ to 10⁻⁹ M, but that 100- to 1,000-foldhigher concentrations of BPI were non-toxic to all of the gram-positivebacterial species, yeasts, and higher eukaryotic cells tested at thattime. It was also reported that BPI at a concentration of 10⁻⁶ M or 160μg/ml had no toxic effect, when tested at a pH of either 7.0 or 5.5, onthe gram-positive organisms Staphylococcus aureus (four strains),Staphylococcus epidermidis, Streptococcus faecalis, Bacillus subtilis,Micrococcus lysodeilacus, and Listeria monocylogenes. BPI at 10⁻⁶ Mreportedly had no toxic effect on the fungi Candida albicans and Candidaparapsilosis at pH 7.0 or 5.5, and was non-toxic to higher eukaryoticcells such as human, rabbit and sheep red blood cells and several humantumor cell lines. See also Elsbach and Weiss, Advances in InflammationResearch, ed. G. Weissmann, Vol. 2, pages 95-113 Raven Press (1981).This reported target cell specificity was believed to be the result ofthe strong attraction of BPI for lipopolysaccharide (LPS), which isunique to the outer membrane (or envelope) of gram-negative organisms.

The precise mechanism by which BPI kills gram-negative bacteria is notyet completely elucidated, but it is believed that BPI must first bindto the surface of the bacteria through hydrophobic and electrostaticinteractions between the cationic BPI protein and negatively chargedsites on LPS. LPS has been referred to as "endotoxin" because of thepotent inflammatory response that it stimulates, i.e., the release ofmediators by host inflammatory cells which may ultimately result inirreversible endotoxic shock. BPI binds to lipid A, reported to be themost toxic and most biologically active component of LPS.

In susceptible gram-negative bacteria, BPI binding is thought to disruptLPS structure, leading to activation of bacterial enzymes that degradephospholipids and peptidoglycans, altering the permeability of thecell's outer membrane, and initiating events that ultimately lead tocell death. [Elsbach and Weiss (1992), supra]. BPI is thought to act intwo stages. The first is a sublethal stage that is characterized byimmediate growth arrest, permeabilization of the outer membrane andselective activation of bacterial enzymes that hydrolyze phospholipidsand peptidoglycans. Bacteria at this stage can be rescued by growth inserum albumin supplemented media [Mannion et al., J. Clin. Invest.,85:853-860 (1990)]. The second stage, defined by growth inhibition thatcannot be reversed by serum albumin, occurs after prolonged exposure ofthe bacteria to BPI and is characterized by extensive physiologic andstructural changes, including apparent damage to the inner cytoplasmicmembrane.

Initial binding of BPI to LPS leads to organizational changes thatprobably result from binding to the anionic groups in the KDO region ofLPS, which normally stabilize the outer membrane through binding of Mg⁺⁺and Ca⁺⁺. Attachment of BPI to the outer membrane of gram-negativebacteria produces rapid permeabilization of the outer membrane tohydrophobic agents such as actinomycin D. Binding of BPI and subsequentgram-negative bacterial killing depends, at least in part, upon the LPSpolysaccharide chain length, with long O-chain bearing, "smooth"organisms being more resistant to BPI bactericidal effects than shortO-chain bearing, "rough" organisms [Weiss et al., J. Clin. Invest. 65:619-628 (1980)]. This first stage of BPI action, permeabilization of thegram-negative outer envelope, is reversible upon dissociation of theBPI, a process requiring the presence of divalent cations and synthesisof new LPS [Weiss et al., J. Immunol. 132: 3109-3115 (1984)]. Loss ofgram-negative bacterial viability, however, is not reversed by processeswhich restore the envelope integrity, suggesting that the bactericidalaction is mediated by additional lesions induced in the target organismand which may be situated at the cytoplasmic membrane [Mannion et al.,J. Clin. Invest. 86: 631-641 (1990)]. Specific investigation of thispossibility has shown that on a molar basis BPI is at least asinhibitory of cytoplasmic membrane vesicle function as polymyxin B [In'tVeld et al., Infection and Immunity 56: 1203-1208 (1988)] but the exactmechanism as well as the relevance of such vesicles to studies of intactorganisms has not yet been elucidated.

Three separate functional domains within the recombinant 23 kDN-terminal BPI sequence have been discovered [Little et al., J. Biol.Chem. 269: 1865 (1994)]. These functional domains of BPI designate aregion of the amino acid sequence of BPI that contributes to the totalbiological activity of the protein and were essentially defined by theactivities of proteolytic cleavage fragments, overlapping 15-merpeptides and other synthetic peptides. Domain I is defined as the aminoacid sequence of BPI comprising from about amino acid 17 to about aminoacid 45. Peptides based on this domain are moderately active in both theinhibition of LPS-induced LAL activity and in heparin binding assays,and do not exhibit significant bactericidal activity. Domain II isdefined as the amino acid sequence of BPI comprising from about aminoacid 65 to about amino acid 99. Peptides based on this domain exhibithigh LPS and heparin binding capacity and are bactericidal. Domain II isdefined as the amino acid sequence of BPI comprising from about aminoacid 142 to about amino acid 169. Peptides based on this domain exhibithigh LPS and heparin binding activity and are bactericidal. Thebiological activities of functional domain peptides may include LPSbinding, IPS neutraization, heparin binding, heparin neutralization orbactericidal activity.

Fungi are eukaryotic cells that may reproduce sexually or asexually andmay be biphasic, with one form in nature and a different form in theinfected host. Fungal diseases are referred to as mycoses. Some mycosesare endemic, i.e. infection is acquired in the geographic area that isthe natural habitat of that fungus. These endemic mycoses are usuallyself-limited and minimally symptomatic. Some mycoses are chieflyopportunistic, occurring in immunocompromised patients such as organtransplant patients, cancer patients undergoing chemotherapy, burnpatients, AIDS patients, or patients with diabetic ketoacidosis.

Fungal infections are becoming a major health concern for a number ofreasons, including the limited number of anti-fungal agents available,the increasing incidence of species resistant to older anti-fungalagents, and the growing population of immunocompromised patients at riskfor opportunistic fungal infections. The incidence of systemic fungalinfections increased 600% in teaching hospitals and 220% in non-teachinghospitals during the 1980's. The most common clinical isolate is Candidaalbicans (comprising about 19% of all isolates). In one study, nearly40% of all deaths from hospital-acquired infections were due to fungi.[Sternberg, Science, 266:1632-1634 (1994).]

Anti-fungal agents include three main groups. The major group includespolyene derivatives, including amphotericin B and the structurallyrelated compounds nystatin and pimaricin. These are broad-spectrumanti-fungals that bind to ergosterol, a component of fungal cellmembranes, and thereby disrupt the membranes. Amphotericin B is usuallyeffective for systemic mycoses, but its administration is limited bytoxic effects that include fever and kidney damage, and otheraccompanying side effects such as anemia, low blood pressure, headache,nausea, vomiting and phlebitis. The unrelated anti-fungal agentflucytosine (5-fluorocytosine), an orally absorbed drug, is frequentlyused as an adjunct to amphotericin B treatment for some forms ofcandidiasis and cryptococcal meningitis. Its adverse effects includebone marrow depression with leukopenia and thrombocytopenia.

The second major group of anti-fungal agents includes azole derivativeswhich impair synthesis of ergosterol and lead to accumulation ofmetabolites that disrupt the function of fungal membrane-bound enzymesystems (e.g., cytochrome P450) and inhibit fungal growth. Significantinhibition of mammalian P450 results in significant drug interactions.This group of agents includes ketoconazole, clotrimazole, miconazole,econazole, butoconazole, oxiconazole, sulconazole, terconazole,fluconazole and itraconazole. These agents may be administered to treatsystemic mycoses. Ketoconazole, an orally administered imidazole, isused to treat nonmeningeal blastomycosis, histoplasmosis,coccidioidomycosisandparacoccidioidomycosis in non-immunocompromisedpatients, and is also useful for oral and esophageal candidiasis.Adverse effects include rare drug-induced hepatitis; ketoconazole isalso contraindicated in pregnancy. Itraconazole appears to have fewerside effects than ketoconazole and is used for most of the sameindications. Fluconazole also has fewer side effects than ketoconazoleand is used for oral and esophageal candidiasis and cryptococcalmeningitis. Miconazole is a parenteral imidazole with efficacy incoccidioidomycosis and several other mycoses, but has side effectsincluding hyperlipidemnia and hyponatremia.

The third major group of anti-fungal agents includesallylamines-thiocarbamates, which are generally used to treat skininfections. This group includes tolnaftate and naftifme.

Another anti-fungal agent is griseofulvin, a fungistatic agent which isadministered orally for fungal infections of skin, hair or nails that donot respond to topical treatment.

Most endemic mycoses are acquired by the respiratory route and areminimally symptomatic; cough, fever, headache, and pleuritic pain may beseen. Occasionally, endemic mycoses may cause progressive pulmonarydisease or systemic infection. Histoplasmosis, caused by Histoplsma, isthe most common endemic respiratory mycosis in the United States; over40 million people have been infected. The disease is noncontagious andordinarily self-limited, but chronic pulmonary infection anddisseminated infection may occur. Pulmonary infection rarely requirestreatment, but disseminated infection may be treated with amphotericinB. Coccidioidomycosis, caused by Coccidioides, is a noncontagiousrespiratory mycosis prevalent in the southwest United States. It also isusually self-limited but may lead to chronic pulmonary infection ordisseminated infection. Amphotericin B or miconazole may be given fortreatment. Blastomycosis, caused by Blastomyces is a noncontagious,subacute or chronic endemic mycosis most commonly seen in the southeastUnited States. Most pulmonary infections are probably self-limited.Patients with progressive lung disease or disseminated disease, andimmunocompromised patients, may be treated systemically withamphotericin B. Paracoccidioidomycosis, caused by Paracoccdioides, is anoncontagious respiratory mycosis that is the most common systemicmycosis in South America. It may be acute and self-limited or mayproduce progressive pulmonary disease or extrapulmonary dissemination.Disseminated disease is generally fatal in the absence of therapy.Sulfonamides may be used but have a low success rate. Amphotenicin Bproduces a higher response rate but relapses may still occur.

Cryptococcosis is a noncontagious, often opportunistic mycosis. It ischaracterized by respiratory involvement or hematogenous dissemination,often with meningitis. A major etiologic agent is C. neoformans. Mostpulmonary infections are probably overlooked, but cryptococcalmeningitis, which accounts for 90% of reported disease, is dramatic andseldom overlooked. Cryptococcosis is a particular problem inimmunocompromised patients; cryptococcal meningitis occurs in 7 to 10%of AIDS patients. The principal symptom of meningitis is headache;associated findings include mental changes, ocular symptoms, hearingdeficits, nausea, vomiting, and seizures. Without treatment, 80% ofpatients die within two years. In meningitis, cryptococci can beobserved in India ink preparations of cerebrospinal fluid sediment, andcan be cultured from the cerebrospinal fluid. Treatment is generallywith fluconazole or the combination of amphotericin B and flucytosine,although amphotericin B does not cross the blood brain barrier.

Aspergillosis is a term that encompasses a variety of disease processescaused by Aspergillus species. Aspergillus species are ubiquitous; theirspores are constantly being inhaled. Of the more than 300 species known,only a few are ordinarily pathogenic for man: A. fumigatus, A. flaws, A.niger, A. nidulans, A. terreus, A. sydowi, A. flavatus, and A. glaucus.Aspergillosis is increasing in prevalence and is particularly a problemamong patients with chronic respiratory disease or immunocompromisedpatients. Among immunocompromised patients, aspergillosis is second onlyto candidiasis as the most common opportunistic mycosis and accounts forabout 15% of the systemic mycoses in this group. Opportunistic pulmonaryaspergillosis is characterized by widespread bronchial erosion andulceration, followed by invasion of the pulmonary vessels, withthrombosis, embolization and infarction. Clinically, infection manifestsas a necrotizing patchy bronchopneumonia, sometimes with hemorrhagicpulmonary infarction. In about 40% of cases, there is hematogenousspread to other sites. Aspergillosis is also a rare but devastatingcomplication of burn wounds; amputation is often required for cure.Invasive aspergillosis is commonly fatal, so aggressive diagnosis andtreatment is required. Blood, urine and cerebrospinal fluid cultures arerarely positive, but fungi can be seen in smears and biopsies.Amphotericin B can be given for treatment.

Mucormycosis is an acute suppurative opportunistic mycosis that producesrhinocerebral, pulmonary or disseminated disease in immuno-compromisedpatients, and local or disseminated disease in patients with burns oropen wounds. Infection is caused by fungi in the class Zygomycetes, andinclude Basidiobolus, Conidiobolus, Rhizopus, Mucor, Absidia,Mortierella, Cunninghamella, and Saksenaea. Rhinocerebral mucormycosisaccounts for about half of all cases of mucormycosis. It is one of themost rapidly fatal fungal diseases, with death occurring within 2-10days in untreated patients. Early clinical signs include nasalstuffiness, bloody nasal discharge, facial swelling and facial pain. Theinfection then spreads to the eyes, cranial nerves and brain. Pulmonarymucormycosis is nearly as common as rhinocerebral disease and manifestswith the same necrotizing and infarction as aspergillosis. Fungi arevirtually never seen or cultured from blood, sputum or cerebrospinalfluid. Disseminated mucormycosis may follow pulmonary or burn woundinfection. Treatment is with amphotericin B.

Candidiasis is a general term for a variety of local and systemicprocesses caused by colonization or infection of the host by species ofthe yeast Candida. Candidiasis occurs worldwide; superficial infectionsof the skin, mouth and other mucus membranes are universal. Invasivesystemic disease has become a problem due to the use of high doses ofantibiotics that destroy normal bacterial flora, immunosuppressiveagents, and agents toxic to bone marrow, e.g., during cancer therapy.Neutropenia is a major risk factor for Candida dissemination.Candidiasis is also seen among immunocompromised individuals such asAIDS patients, organ transplant patients, patients receiving parenteralnutrition, and cancer patients undergoing radiation treatment andchemotherapy. It is the most common opportunistic mycosis in the world.The most common etiologic agent is Candida albicans. Other infectiousspecies include C. tropicalis, C. parapsilosis, C. stellatoidea, C.krusei, C. parakrusei, C lusitaniae, C. pseudorropicalis, C.guilliermondi and C. glabrata. Candida albicans is normally found in themouth, throat, gastrointestinal tract and vagina of humans. Non-albicansspecies frequently colonize skin. Candida species occur in two formsthat are not temperature- or host-dependent. The usual colonizing formsare yeasts that may assume a pseudomycellal configuration, especiallyduring tissue invasion. Pseudomyceliae result from the sequentialbudding of yeasts into branching chains of elongated organisms.

Candida albicans contains cell wall mannoproteins that appear to beresponsible for attachment of the yeast cells to specific host tissues.It has been reported that the mannan portion, rather than the proteinportion, of the mannoproteins is responsible for adherence of fungalcells to spleen and lymph node tissues in mice. [Kanbe et al., InfectionImmunity, 61:2578-2584 (1993).]

C. albicans also binds avidly to extracellular matrix (ECM) proteinssuch as fibronectin, laminin, and types I and IV collagen, all of whichcontain heparin-binding domains. This suggests C. albicans may express aheparin-like surface molecule. Adherence of C. albicans to the ECM maybe important in the pathogenesis of disseminated candidiasis. It hasbeen demonstrated that heparin, heparan sulfate and dextran sulfateglycosaminoglycans (GAGs) inhibit adherence of C. albicans to ECM andECM proteins, possibly by a mechanism involving binding of GAGs to ECMproteins, thus masking these selective ligands. [Klotz et al., FEMSMicrobiology Leters, 78:205-208 (1992).]

Clinically, candidiasis manifests as superficial mucocutaneousinfections, chronic mucocutaneous candidiasis, or systemic infection.Superficial mucocutaneous infections can occur in any area of skin ormucus membrane. Thrush, commonly seen in AIDS patients, is characterizedby a patchy or continuous, creamy to gray pseudomembrane that covers thetongue, mouth, or other oropharyngeal surfaces and may be accompanied byulceration and necrosis. Layngeal involvement results in hoarseness.Esophagitis is often an extension of oropharyngeal disease and maymanifest with symptoms of retrostemal pain and dysphagia. Intestinalcandidiasis is commonly asymptomatic, but is a major source ofhematogenous invasion in immunocompromised individuals. Intertrigoinvolves the axillae, groins, infmamarmary folds, and other warm, moistareas, and may manifest as red, oozing or dry, scaly lesions. Infectionsmay occur in other areas, including perianal and genital areas.Paronychia, infection of the nails, often follows chronic exposure ofthe hands or feet to moisture. Some patients with limited T-cellimmunodeficiency develop chronic mucocutaneous candidiasis. Thesepatients suffer from persistent superficial Candida infection of theskin, scalp, nails and mucus membranes.

Most cases of systemic candidiasis are caused by Candida albicans and C.tropicalis, and increasingly, C. glabrata. Clinical manifestations ofCandida infection appear mainly in the eyes, kidneys and skin. In theeyes, there may be single or multiple raised, white, fluffychorioretinal lesions. These lesions are a potential cause of blindness.Involvement of the kidneys includes diff-use abscesses, capillarynecrosis and obstruction of the ureters. Infection may result inprogressive renal insufficiency. Systemic Candida infection can alsomanifest as maculonodular skin lesions surrounded by a reddened area;these lesions have an appearance similar to acne but are a major clue toa potentially lethal disease. Other manifestations of systemiccandidiasis may include osteomyelitis, arthritis, meningitis, andabscesses in the brain, heart, liver, spleen and thyroid. Involvement ofthe lungs is also common, but pulmonary lesions are usually too small tobe seen on chest X-ray. Finally, Candida endocarditis can occur inpatients receiving prolonged intravenous therapy or cardiac valveimplants, or in intravenous drug abusers. Fungal lesions appear on thevalves, and can embolize and occlude large blood vessels.

Superficial infections are diagnosed by microscopic examination ofscrapings or swabs of infected lesions in the presence of 10% potassiumhydroxide. Canada organisms can also be seen on gram stain. Endocarditisis diagnosed by blood cultures or demonstration of bulky valvularlesions on echocardiography. Systemic candidiasis may be difficult todiagnose because the presence of heavy colonization at the usual sitesof infection indicates, but does not prove, that dissemination hasoccurred. The most reliable evidence of systemic candidiasis is biopsydemonstration of tissue invasion or recovery of yeast from fluid in aclosed body cavity, such as cerebral spinal fluid, pleural or peritonealfluid. Similarly, positive blood or urine or sputum cultures mayindicate invasive disease or simply localized disease around indwellingdevices, e.g., catheters or intravenous lines.

Mucocutaneous infections may be treated with topical preparations ofnystatin, amphotericin B, clotrimazole, miconazole, haloprogin orgentian violet. Oropharyngeal or esophageal candidiasis can be treatedwith systemic agents such as ketoconazole or fluconazole. Chronicmucocutaneous candidiasis syndrome may respond to topical or systemictherapeutic agents such as amphotericin B or ketoconazole, but oftenrelapses when medication is discontinued. Cystitis may be treated withamphotericin B bladder rinses, or a brief low-dose intravenous course ofamphotericin B with or without oral flucytosine. Endocarditis isessentially incurable without valve replacement, accompanied by a 6 to10 week course of amphotericin B and flucytosine. Even with therapy,however, complete cure of endocarditis is not always possible.

The mortality rate from systemic candidiasis is about 50%. Systemiccandidiasis may be treated with fluconazole, a fungistatic agent, oramphotericin B, a fungicidal agent although systemic use of the latteris limited by its toxicity. Both drugs have substantial adversereactions when used in combination with cyclosporine A, which itself canbe nephrotoxic. The removal of precipitating factors such as intravenouslines or catheters is also important for controlling infection.Flucytosine therapy can be added to the amphotericin B therapy fortreatment of systemic candidiasis, especially in patients that are notimmunocompromised. In immunocompromised patients, however, theseinfections are problematic and resist effective treatment. Mortalitywith systemic candidiasis can be over 90% in such patients. Furthermore,chronic mucocutaneous candidiasis and candidal endocarditis often showevidence of disease after having been declared cured.

There continues to exist a need in the art for new anti-fungal methodsand materials. In particular, effective anti-fungal therapy for systemicmycoses is limited. Products and methods responsive to this need wouldideally involve substantially non-toxic compounds available in largequantities by means of synthetic or recombinant methods. Ideal compoundswould have a rapid effect and a broad spectrum of fungicidal orfungistatic activity against a variety of different fungal species whenadministered or applied as the sole anti-fungal agent. Ideal compoundswould also be useful in combinative therapies with other anti-fungalagents, particularly where these activities would reduce the amount ofanti-fungal agent required for therapeutic effectiveness, enhance theeffect of such agents, or limit potential toxic responses and high costof treatment.

SUMMARY OF THE INVENTION

The present invention provides novel peptides derived from or based onDomain III (amino acids 142-169) of bactericidal/permeability-increasingprotein (BPI) and therapeutic uses of such peptides as anti-fungalagents. Peptides of the invention are useful in methods of treating asubject suffering from a fungal infection by administering atherapeutically effective amount of the peptide. This is based on thesurprising discovery that Domain III derived peptides havefungicidal/fungistatic effects. A second surprising discovery is thatsuch peptides have LPS-neutralizing activity. This activity provides anadditional benefit in the use of peptides of the invention for treatingfungal infections. Domain mI derived peptides may be administered aloneor in conjunction with known anti-fungal agents. When made the subjectof adjunctive therapy, the administration of Domain III derived peptidesmay reduce the amount of anti-fungal agent needed for effective therapy,thus limiting potential toxic response and/or high cost of treatment.Administration of Domain III derived peptides may also enhance theeffect of such agents, accelerate the effect of such agents, or reverseresistance of fungi to such agents. Peptides according to the inventioninclude peptides SEQ ID NOS:1-250.

In addition, the invention provides a method of killing or inhibitinggrowth of fungi comprising contacting the fungi with a Domain IIIderived peptide. This method can be practiced in Vivo or in a variety ofin vitro uses such as to decontaminate fluids and surfaces and tosterilize surgical and other medical equipment and implantable devices,including prosthetic joints and indwelling invasive devices.

A further aspect of the invention involves use of a Domain III derivedpeptide for the manufacture of a medicament for treatment of fungalinfection. The medicament may include, in addition to a Domain mIderived peptide, other chemotherapeutic agents such as anti-fungalagents.

Numerous additional aspects and advantages of the invention will becomeapparent to those skilled in the art upon considering the followingdetailed description of the invention, which describes the presentlypreferred embodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides results of broth assay tests of the activity of variouspeptides against C. albicans.

FIGS. 2A and 2B provide results of radial difflusion assays of theactivity of various peptides against C. albicans SLU-1 (FIG. 2A) and C.albicans SLU-2G (FIG. 2B).

FIG. 3 provides results of broth assay tests of the activity ofcombinations of peptide and amphotericin B against C. albicans.

FIGS. 4, 5, and 6 graphically represent survival data in mice after C.albicans challenge and treatment with peptides or buffer control.

FIGS. 7 graphically represents survival data in cyclosporin-treated miceafter C. albicans challenge and treatment with peptides or buffercontrol.

FIG. 8 provides results of RAW cell assay tests of the activity ofvarious peptides.

FIG. 9 graphically represents survival data in mice after challenge withE. coli 0111 :B4 LPS and treatment with peptide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the surprising discovery that a DomainIII derived peptide has fungicidal activity and can be administered totreat subjects suffering from fungal infection. As used herein,"subject" is meant to refer to higher organisms, including animals(e.g., humans; companion animals such as dogs; livestock such as horses,cows and pigs; poultry; insects; fish; avian species) and plants. Alsoprovided are methods of treating fungal infections with such peptides.Unexpectedly, Domain III derived peptides were demonstrated to haveanti-fungal activities both in in vitro killing assays and in in vivomodels of fungal infection, as measured, for example, by improvedsurvival or reduction of colony-forming units in circulation afterfungal challenge. A variety of fungal infections, including infectionscaused by Aspergillus, infections caused by Cryprococcus, such ascryptococcal meningitis, and mucocutaneous and systemic candidiasiscaused by Canada species, may be treated according to the invention.Also, unexpectedly, Domain III derived peptides were demonstrated tohave LPS-neutralizing activity both in an in virro assay and an in vivomodel. This activity provides an additional benefit in the treatment offungal infections where bacterial LPS from translocation or additionalinfection is associated with the fungal infection.

As used herein "Domain III derived peptide" includes peptides having anamino acid sequence of BPI protein from about position 142 to aboutposition 169, subsequences thereof and variants of the sequence orsubsequence thereof, which posses antifungal activity. Specificallyincluded are those antifungal peptides having six to fourteen aminoacids and having the amino acid sequence of BPI protein from aboutposition 148 to about position 161, subsequences thereof and variants ofthe sequence or subsequence. amino acid sequence of BPI protein fromabout position 148 to about position 161, subsequences thereof andvariants of the sequence or subsequence. Certain preferred peptides havefourteen amino acids and among the preferred variant sequences andsubsequences are those having K as an amino acid corresponding to G atposition 152. Preferred peptide sequences with fourteen amino acids havea core amino acid sequence selected from the group consisting of LIQL,IQLF, WUQL, LIQLF and WLIQLF or a variant core amino acid sequencehaving at least 75% homology to said core amino acid sequence andinclude the peptides of SEQ ID NOS: 4 (XMP.13), 6-19 (XMP.31-44), 21-22(XMP.82-83), 23-25 (.85-87),26-27 (XM:P.91-92), 28-31 (XMP.94-97), 32-33(XMP.100-101), 34 (XMP.104), 35-40 (XMP.106-111), 41 (.113), 42(XMP.116), 43-55 (XMP.123-135), 57-58 (tX].138-139), 59-61(XMP.142-144), 62 (XMP.146), 66-78 (XMP.222-234), 80-88 (XMP.236-244),89-109 (XMP.249-269) and 116 (XMP.283). This group of antifungal 14 merpeptides includes variant sequence peptides wherein at least one BPIsequence residue has been replaced by a D-isomer amino acid. See, e.g.,SEQ ID NOS: 46(XMP.126), 48 (XMP.128), 86-87 (MP.242-243) and 92-93(XMP.252-253). Variants involving BPI sequence replacements by atypicalamino acids such as β(1-naphthyl)A, β(2-naphthyl)A, para-amino F,cyclohexyl A, α- and -γ-aminobutyric acids, α methyl A and N-methyl G, Vand L are also included within this group.

Among the presently preferred Domain III derived antifungal peptides ofthe invention having from seven to twelve amino acids comprising: (a) acore sequence of amino acids selected from the group consisting of LIQL,IQLF, WLIQL, LIQLF and WLIQLF; and (b) one or more cationic amino acidsselected from the group consisting of K, R, H, ornithine anddiaminobutyric acid at the amino and/or carboxy terminal portion of thecore sequence. A subset of peptides have from seven to nine amino acidscomprising: (a) a core sequence of amino acids selected from the groupconsisting of LIQL and IQLF; and (b) at least two cationic amino acidsselected from the group consisting of K, R, H, ornithine anddiaminobutyric acid at the amino and/or carboxy terminal portion of thecore sequence. Another subset of peptides has from eight to ten aminoacids comprising: (a) a core sequence of amino acids selected from thegroup consisting of LIQLF and WLIQLF; and (b) at least two cationicamino acids selected from the group consisting of K, R, H, ornithine anddiaminobutyric acid at the amino and/or caioxy terminal portion of thecore sequence. Still another subset of peptides has nine to twelve aminoacids comprising: (a) a core sequence of amino acids selected from thegroup consisting of WLIQLF; and (b) at least three cationic amino acidsselected from the group consisting of K, R, H, omnithine anddiaminobutyric acid at the amino and/or carboxy terminal portion of thecore sequence. Illustrating these subsets are the peptides of SEQ IDNOS: 118-137 (XMP.285-304), 140-144 (XMP.307-311), 155-160(XMP.322-327), 166-170 (XMP.335-339), 174-177 (XMP.343-346), 179-184(XMP.348-353), 186 (XMP.355), 188-190 (XMP.357-359).

It will be apparent from consideration of the structures of theabove-described peptides that the Domain III sequence of BPI amino acidsfrom 148 to 161 includes the core sequence(s) noted above as well asmultiple cationic residues (K and H) flanking the core. This motif iscarried forward in the structures of subsequences of the 148 to 161sequence providing antifungal peptides of the invention and alsopreserved in antifungal variants of the 148 to 161 sequence andsubsequences thereof. Note, for example that when the G residue normallyin the BPI sequence at position 152 is replaced by K, this replacementserves to provide a cationic residue immediately adjacent to thepredominantly hydrophobic core residues. Sequence and subsequencevariants providing antifungal peptides according to the invention thusinclude those peptides wherein one or more existing non-cationicresidues ordinarily flanking the core sequence(s) are replaced bycationic residues. 158) are replaceable by a different aromatic aminoacid residues or by neutral aliphatic residues G, A, V, I and L.Moreover, the core sequence Q (BPI residue 156) is replaceablepreferably by a neutral hydrophilic amino acid T, S and N. As notedabove, where variations are introduced into core subsequence(s), it ispreferable that the variant core sequence(s) retain 75% homology to thesequences occurring in BPI.

Antifungal Domain III peptides of the invention have one or moreD-isomer amino acids, as illustrated by the peptides of SEQ ID NOS: 164(MP.333), 165 (XMP.334), 173 (XMP.342), 194 (MP.363) and 196 (XMP.365)and have the core sequence amino acids comprise D-isomer amino acids inreverse sequence order as illustrated by peptides having the amino acidsequence set out in SEQ ID NOS: 163 X.332) and 198 (XMP.367). Theantifungal peptides can have an acetylated amino terminal amino acidresidue as illustrated by the peptides of SEQ ID NOS: 162 (P.331), 185(XMP.354), 187 (XMP.356), 195 (XMP.364), 199 (XMP.368) and 204(XMP.373). Cyclic antifungal peptides as illustrated by SEQ ID NOS:191-193 (XMP.360-362) are also within the scope of the invention.

Additional Domain in antifungal peptides of the invention includeantifungal peptides SEQ ID NOS: 1 (XMP.5), 2-4 (XMP.11-.13), 5 (XMP.29),20 (P.55), 56 (XMP.137), 79 (XMP.235), 111-115 (XMP.271-.275), 117(XMP.284), 132 (XMP.299), 138-139 (MP.305-.306), 145-154 (XMP.312-321),200-203 (XMP.369-372), 171-172 (XMP.340-.341) and BPI residues 145-159and 149-163 of SEQ ID NO:206.

Additional Domain In antifungal peptides of the invention includeantifungal peptides SEQ ID NOS:205-243 (XMP.374-.412) and SEQ IDNOS:244-250 (XMP.414-.420). Thus, peptides of the invention includepeptides that have SEQ ID NOS: 1-250 as shown in Table 1 herein.

Pharmaceutical compositions of the invention comprise a Domain IIIderived peptide and a pharmaceutically acceptable diluent, adjuvant orcarrier and are administered topically, intravenously, orally or as anaerosol.

In viro methods of the invention permit killing or inhibitingreplication of fungi through contacting the fungi with an antifungalpeptide or pharmaceutical composition containing the same. Fungalinfection treatment methods of the invention comprise administering to asubject suffering from a fungal infection a therapeutically effectiveamount of a Domain III antifungal peptide and such treatment methods areapplicable to infections by fungal infection involves a fungal speciesselected from the group consisting of Candida (especially, C albicans,C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis and C.tropicalis), Aspergillus and Cryptococcus species.

As described in detail medicaments/pharmaceutical compositions developedaccording to the invention can include other antifungal agents includingnon-peptide agents or can be used in combinative therapeutic methodswith other such agents.

Peptides derived from or based on BPI produced by recombinant orsynthetic means (BPI-derived peptides) have been described in crownedand copending PCT Application No. U.S. Ser. No. 94/10427 filed Sep. 15,1994, which corresponds to U.S. patent application Ser. No. 08/306,473,filed Sep. 15, 1994, and PCT Application No. U.S. Ser. No. 94/02465filed Mar. 11, 1994, which corresponds to U.S. patent application Ser.No. 08/209,762, filed Mar. 11, 1994, which is a continuation-in-part ofU.S. patent application Ser. No. 08/183,222, filed Jan.14, 1994, whichis a continuation-in-part of U.S. patent application Ser. No. 08/093,202filed Jul. 15, 1993 (for which the corresponding internationalapplication is PCT Application No. U.S. Ser. No. 94/02401 filed Mar. 11,1994), which is a continuation-in-part of U.S. patent application Ser.No. 08/030,644 filed Mar. 12, 1993 (disclosing, inter alia, overlapping15-mer peptides having BPI residues 145-159 and 149-163 of SEQ ID NO.206), the disclosures of all of which are incorporated herein byreference. BPI-derived peptides having an amino acid sequence of BPIprotein from about position 142 to about position 169, subsequencesthereof and variants of the sequence or subsequence thereof, whichpossess a BPI anti-fungal biological activity, were disclosed inco-owned and co-pending U.S. priority application Ser. No. 08/372,105filed Jan. 13, 1995, the disclosure of which is incorporated herein byreference.

The Domain III derived peptide may be administered systemically ortopically. Systemic routes of administration include oral, intravenous,intramuscular or subcutaneous injection (including into depots forlong-term release), intraocular or retrobulbar, intrathecal,intraperitoneal (e.g. by intraperitoneal ravage), transpulmonary usingaerosolized or nebulized drug, or transdermal. Topical routes includeadministration in the form of salves, ophthalmic drops, ear drops, orirrigation fluids (for, e.g., irrigation of wounds).

The Domain III derived peptide may be administered in conjunction withother anti-fungal agents. Preferred anti-fungal agents for this purposeare amphotericin B and fluconazole. Concurrent administration of DomainIII derived peptide with anti-fungal agents is expected to improve thetherapeutic effectiveness of the anti-fungal agents. This may occurthrough reducing the concentration of anti-fungal agent required toeradicate or inhibit fungal growth, e.g., replication. Because the useof some agents is limited by their systemic toxicity or prohibitivecost, lowering the concentration of anti-fungal agent required fortherapeutic effectiveness reduces toxicity and/or cost of treatment, andthus allows wider use of the agent. Concurrent administration of DomainIII derived peptide and another anti-fungal agent may produce a morerapid or complete fungicidal/fungistatic effect than could be achievedwith either agent alone. Domain III derived peptide administration mayreverse the resistance of fungi to anti-fungal agents. Domain IIIderived peptide administration may also convert a fungistatic agent intoa fungicidal agent.

An advantage provided by the present invention is the ability to treatfungal infections, particularly Candida infections, that are presentlyconsidered incurable. Another advantage is the ability to treat fungithat have acquired resistance to known anti-fungal agents. A furtheradvantage of concurrent administration of Domain III derived peptidewith an anti-fungal agent having undesirable side effects, e.g.,amphotericin B, is the ability to reduce the amount of anti-fungal agentneeded for effective therapy. The present invention may also providequality of life benefits due to, e.g., decreased duration of therapy,reduced stay in intensive care units or reduced stay overall in thehospital, with the concomitant reduced risk of serious nosocomial(hospital-acquired) infections.

"Concurrent administration" as used herein includes administration ofthe agents together, simultaneously or before or after each other. TheDomain III derived peptide and anti-fungal agents may be administered bydifferent routes. For example, the Domain III derived peptide may beadministered intravenously while the anti-fungal agents are administeredintramuscularly, intravenously, subcutaneously, orally orintraperitoneally. Alternatively, the Domain III derived peptide may beadministered intraperitoneally while the anti-fungal agents areadministered intraperitoneally or intravenously, or the Domain miderived peptide may be administered in an aerosolized or nebulized formwhile the anti-fungal agents are administered, e.g., intravenously. TheDomain in derived peptide and anti-fungal agents may be bothadministered intravenously. The Domain III derived peptide andanti-fungal agents may be given sequentially in the same intravenousline, after an intermediate flush, or may be given in differentintravenous lines. The Domain In derived peptide and anti-fungal agentsmay be administered simultaneously or sequentially, as long as they aregiven in a manner sufficient to allow both agents to achieve effectiveconcentrations at the site of infection.

Concurrent administration of Domain III derived peptide and anotheranti-fungal agent is expected to provide more effective treatment offungal infections. Concurrent administration of the two agents mayprovide greater therapeutic effects in vivo than either agent provideswhen administered singly. For example, concurrent administration maypermit a reduction in the dosage of one or both agents with achievementof a similar therapeutic effect. Alternatively, the concurrentadministration may produce a more rapid or completefungicidal/fungistatic effect than could be achieved with either agentalone.

Therapeutic effectiveness is based on a successful clinical outcome, anddoes not require that the anti-fungal agent or agents kill 100% of theorganisms involved in the infection. Success depends on achieving alevel of anti-fungal activity at the site of infection that issufficient to inhibit the fungi in a manner that tips the balance infavor of the host. When host defenses are maximally effective, theanti-fungal effect required may be minimal. Reducing organism load byeven one log (a factor of 10) may permit the host's own defenses tocontrol the infection. In addition, augmenting an earlyfungicidal/fungistatic effect can be more important than long-termfungicidal/fungistatic effect. These early events are a significant andcritical part of therapeutic success, because they allow time for hostdefense mechanisms to activate.

A Domain III derived peptide may interact with a variety of host defenseelements present in whole blood or serum, including complement, p15 andL1P, and other cells and components of the immune system. Suchinteractions may result in potentiation of the activities of thepeptide. Because of these interactions, Domain III derived peptides canbe expected to exert even greater activity in vivo than in vitro. Thus,while in vitro tests are predictive of in vivo utility, absence ofactivity in vitro does not necessarily indicate absence of activity invivo. For example, BPI has been observed to display a greaterbactericidal effect on gram-negative bacteria in whole blood or plasmaassays than in assays using conventional media. [Weiss et al., J. Clin.Invest. 90:1122-1130 (1992)]. This may be because conventional in vitrosystems lack the blood elements that facilitate or potentiate BPI'sfunction in vivo, or because conventional media contain higher thanphysiological concentrations of magnesium and calcium, which aretypically inhibitors of the activity of BPI protein products.Furthermore, in the host, Domain III derived peptides are available toneutralize translocation of gram-negative bacteria and concomitantrelease of endotoxin, a further clinical benefit not seen in orpredicted by in vitro tests of anti-fungal activity.

It is also contemplated that the Domain II derived peptides beadministered with other products that potentiate the activity of thepeptide, including the anti-fungal activity of the peptides. Forexample, serum complement potentiates the gram-negative bactericidalactivity of BPI protein products; the combination of BPI protein productand serum complement provides synergistic bactericidal/growth inhibitoryeffects. See, e.g., Ooi et al. J. Biol. Chem., 265: 15956 (1990) andLevy et al. J. Biol. Chem., 268: 6038-6083 (1993) which addressnaturally-occurring 15 kD proteins potentiating BPI antibacterialactivity. See also co-owned, co-pending PCT application No. U.S. Ser.No. 94/07834 filed Jul. 13, 1994, which corresponds to U.S. patentapplication Ser. No. 08/274,303 filed Jul. 11, 1994 as acontinuation-in-part of U.S. patent application Ser. No. 08/093,201filed Jul. 14, 1993. These applications, which are all incorporatedherein by reference, describe methods for potentiating gram-negativebactericidal activity of BPI protein products by administeringlipopolysaccharide binding protein (LBP) and LBP protein products. LBPprotein derivatives and derivative hybrids which lack CD-14immunostimulatory properties are described in PCT Application No. U.S.Ser. No. 94/06931 filed Jun. 17, 1994, which corresponds to co-owned,co-pending U.S. patent application Ser. No. 08/261,660, filed Jun. 17,1994 as a continuation-in-part of U.S. patent application Ser. No.08/079,510, filed Jun. 17, 1993, the disclosures of all of which arehereby incorporated by reference. It has also been observed thatpoloxamer surfactants enhance the anti-bacterial activity of BPI proteinproducts, as described in Lambert, U.S. application Ser. No. 08/372, 104filed Jan. 13, 1995; poloxamer surfactants may also enhance the activityof anti-fungal agents.

Without being bound by a theory of the invention, it is believed thatDomain III derived peptides may have several modes of action. Thepeptide, through its heparin-binding ability, may interfere with thebinding of fungi to the extracellular matrix. For example, hepari-likesurface molecules of Canada are believed to mediate adhesion of theyeast to extracellular matrix and host tissues. The peptide may also actdirectly on the cytoplasmic membrane of fungi. In addition, the peptidemay bind to fungal cell wall mainoproteins that are structurally similarto the LPS of gram-negative organisms or that are responsible foradherence to target host tissues, thus interfering with fungalinteraction with host tissues. Binding to fungal mannans may alsopromote access of the peptide to the inner cytoplasmic membrane. Inaddition, because fungal infection may cause stress-inducedtranslocation of bowel flora and/or LPS, the peptide may also actbeneficially by killing gram-negative bacteria and neutralizing LPS.Finally, the antifungal activity of Domain III peptides according to theinvention may result from unique structural features. For example, a sixamino acid sequence within Domain III (WLQLF) and the included five andfour amino acid sequences (LIQL, IQLF, WLIQL and LIQLF) are composed ofhydrophobic amino acids with the exception of glutamine (Q) that is aneutral hydrophilic amino acid. This hydrophobic stretch is bounded byhighly cationic (polar) lysines on the N- and C-termini. This motif isreminiscent of leader/signal peptides as well as transmembrane segmentsof membrane proteins. Aliphatic amino acids such as I, L, V, M, A, havea high propensity to form transmembrane a-helical structures within thehydrophobic membrane environment when found in sequences of 12-15nonpolar amino acids due to their ability to form backbone hydrogenbonds. Aromatic hydrophobic amino acids such as W and F can alsoincorporate into a membrane ae-helix. The neutral, hydrophilic glutaminein the middle of a Domain III hydrophobic stretch may participate inhydrogen bonding with other fungal membrane components such asergosterol and thus play an important role in the fungicidal activity. Ashort 10 amino acid peptide (e.g., XMP.293) is not expected to be longenough to span a lipid bilayer and probably has a much differentmechanism of action than a membrane disrupting, amphipathic type ofcationic antimicrobial peptide. The short motif of six to twelve aminoacid peptides with a core of neutral amino acids bounded by cationicamino acids is not long enough to span a fungal lipid bilayer and thusmay be allowed to traverse the membrane bilayer more efficiently thanlonger peptides. If transported inside the cell, thecationic/neutral/cationic molecules may inhibit the function ofendogenous polyamines (spermidine, spermine, putrescine) by eithercompetitive inhibition of the polyamine regulation of cell wallcarbohydrate synthesis and/or by feedback inhibition of polyaminesynthesis.

In addition, the invention provides a method of killing or inhibitinggrowth of fungi comprising contacting the fungi with a Domain IIIderived peptide. This method can be practiced in Vivo or in a variety ofin vitro uses such as use in food preparations or to decontaminatefluids and surfaces or to sterilize surgical and other medical equipmentand implantable devices, including prosthetic joints. These methods canalso be used for in situ sterilization of indwelling invasive devicessuch as intravenous lines and catheters, which are often foci ofinfection.

A further aspect of the invention involves use of a Domain III derivedpeptide for the manufacture of a medicament for treatment of fungalinfection. The medicament may include, in addition to a BPI proteinproduct, other chemotherapeutic agents such as anti-fungal agents. Themedicament can optionally comprise a pharmaceutically acceptablediluent, adjuvant or carrier.

The administration of antifungal peptides is suitably accomplished witha pharmaceutical composition comprising a peptide and a pharmaceuticallyacceptable diluent, adjuvant, or carrier. The peptide may beadministered without or in conjunction with known surfactants, otherchemotherapeutic agents or additional known anti-fungal agents.

Other aspects and advantages of the present invention will be understoodupon consideration of the following illustrative examples whereinExample 1 addresses peptide preparation and purification; Example 2addresses in vitro anti-fungal testing of peptides; Example 3 addressesadditional in vitro and in vivo testing of the anti-fungal effect ofpeptides on a variety of fungal species, including Candida strains andantibiotic resistant strains; Example 4 addresses the in vivo effect ofpeptides on survival of mice challenged with Candida; Example 5addresses the serum stability of peptides; Example 6 addresses thedesign and assay of anti-fungal peptides for structural motif andminimum functional sequence analysis; Example 7 addresses LPSneutralization activities of anti-fungal peptides; and Example 8addresses peptide formulations.

EXAMPLE 1 Peptide Preparation and Purification

This example addresses the preparation and purification of Domain IIIderived peptides.

Peptides may be prepared according to a variety of synthetic procedures.Some peptides (e.g., XMP.5) were prepared by solid phase peptidesynthesis as described in parent U.S. patent application Ser. Nos.08/209,762 and 08/183,222 according to the methods of Merrifield, J. AmChem. Soc. 85: 2149 (1963) and Merrifield et al. Anal. Chem., 38:1905-1914 (1966) using an Applied Biosystems, Inc. Model 432 peptidesynthesizer.

Alternatively, peptides were synthesized on a larger scale using solidphase peptide synthesis on an Advanced Chemtech (ACT-Model 357 MPS)synthesizer utilizing a 1-Fluorenylmethyl-oxycarbonyl (Fmoc) protectionstrategy with a double coupling procedure employingN,N-diisopropylcarbodiimide (DIC)/1-hydroxybenzotriazole (ROBt) and2-(1-H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumhexa-fluorophosphate (HBTU)/HOBt/diisopropylethylamine (DIEA). The solidsupport used was a polystyrene resin with 1% divinylbenzene (DVB)cross-linking and an 4-(2', 4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy(Fmoc-Rink amide) linker with a substitution rate of 0.44 mmoles/gram.The scale used was between 0.1 grams and 5 grams of starting resin.

Dimethylformamide (DMF) was the primary solvent with a 50/50 solution ofpiperidine/DMF used for Fmoc deprotection in three consecutivetreatments of 1, 5, and 10 minutes, respectively. A double couplingprocedure was used in each cycle with a 4:1 amino acid to peptide ratioused in each coupling. The amino acids were dissolved in a 0.5 M HOBtsolution in N-methylpyrrolidinone (NMP) at a concentration also of 0.5M. For the first coupling, an equimolar (to amino acid) amount of a 0.5M solution of diisopropylcarbodiimide (DIPCDI) in NMP was used andallowed to react for 45 minutes. The second coupling utilized anequimolar (to amino acid) volume of a 0.5M HBTU solution in DMF with anequal volume of a 1 M DIHA solution in NMP (2:1, DIEA:amino acid) for aperiod of 30 minutes.

Upon completion of the synthesis, the resin was treated with MeOH, driedunder vacuum, and then cleaved using a cocktail composed oftrifluoroacetic acid (IFA):thioanisole:ethanedithiol (EDT):water, at aratio of 36:2:1:1 (volume was dependent on the amount of resin) for aminimum of 2 hours with an additional 30 minutes added for each arginine(but not excecding 3 hours) with the first 15 minutes occurring in a wetice bath. The solutions were then dissolved in a 10% TPA in watersolution, washed 3 times with methyl t-butyl ether (IBE) andlyophilized.

The amino termini of selected peptides were acetylated after synthesison solid phase using an N-terminal Fmoc protection strategy as describedabove. Subsequent to Fmoc removal with piperidine and prior to peptidecleavage with TFA, the peptide on the resin was derivatized with a10-fold molar excess of acetic anhydride with a 2-fold molar excess ofdiisopropylethylamine in dimethylformamide for one hour or a doublecoupling procedure employing N,N-diisopropylcarbodiimide(DIC)/1-hydroxybenzotriazole (HOBt) and 2-(1-H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexa-fluorophosphate(EBTU)/HOBt/diisopropylethylamine (DIEA) and one of the followingbuilding blocks was used for derivatization: caprylic acid, lauric acid,Fmoc-8-amino-ctonoic acid and FMoc-12-amino-dodecanoic acid. The peptidewas then cleaved from the resin with the TFA cleavage cocktail asdescribed above and purified as described below. N-terminal acacylationof the purified peptide was verified by mass spectrometry.

For purity analysis of each newly synthesized peptide, dilute solutionsof crude lyophilized peptides were prepared and analyzed on a MichromUltrafast Microprotein Analyzer equipped with a 150 mm×1 mm, 5 μparticle, 300 Å pore C-8 Zorbax column. The column oven was set to 40°C., the flow rate was 100 μL/minute, and injection volumes weretypically 5-10 μL. HPLC was performed using 5% acetonitrile/0.1% TFA inwater as mobile phase A, and 80% acetonitrile/0.065% TFA as mobile phaseB. The eluate was monitored spectrophotometrically at 214 nm. Percentpurity is calculated from the peak area of the individual peptides (seeTable 1).

Selected peptides were purified by high performance liquidchromatography (HPLC), using a Waters Prep LC 2000 PreparativeChromatography System (Water Corp., Milford, Mass.) equipped with aDelta Pak C-18, 15 μm, 300 A cartridge column consisting of a 40×10 mmguard cartridge and a 40×100 mm Prep Pak cartridge. The column wasequilibrated in 25% buffer B, where A=5% acetonitrilel0.1%trifluoroacetic acid and B=80% acetonitrile/0.065% trifluoroacetic acid.Peptides were dissolved to ˜20 mg/mL in buffer A and 200-800 mg wereapplied to the column through the LC pump operating at a flow rate of8-17 mL/minute bound material was eluted with a gradient of 25-35%buffer B/30 min applied at 8-17 mL/minute. (Some peptides were purifiedwith a gradient of 23-33%B/30 minute). The eluate was monitored at 220and/or 280 and 300 nm with a Waters 490E Programmable MultiwavelengthDetector. Fractions were collected and assayed for the peptide ofinterest on an Ultrafast Micoprotein Analyzer (Michrom BioResources,Inc., Pleasanton, Calif.) equipped with a Zorbax C-8, 150×1 mm, 5 μm,300 Å maintained at 40° C. Fractions containing the peptide of interestat ≧95% purity were pooled and lyophilized to dryness. The purity of therecovered material was determined with analytical reverse-phase HPLC.

EXAMPLE 2 In Vitro Anti-Fungal Effects

This example addresses in vitro screening of Domain III derived peptidesfor anti-fungal activity in a broth assay and/or in a radial diffusionassay.

Table 1 below sets out peptides derived from or based on Domain III BPIsequences. Such peptides may be identified by peptide number with aprefix XMP or BPI (e.g., XMP.1 or BPI.1, XMP.2 or BPI.2, etc.). Table 1also sets out the SEQ ID NO: of each peptide, the amino acid sequencebased on reference to position within BPI and the designation of aminoacid substitutions and additions. Also set out in Table 1 are HPLCestimates of purity of the peptides. The HPLC purity analysis wasperformed as described in Example 1.

In each broth assay screening procedure, a colony of C. albicansdesignated CA-1, Strain SLU-1 that was received from the laboratories ofG. Matuschak and A. Lechner, St. Louis University Hospital, St. Louis,Mo., where the strain was maintained, was inoculated into a tubecontaining 5 mL Sabouraud Dextrose broth (2% dextrose, 1% neopeptone)and incubated overnight at 37° C. with shaking. The overnight culturewas diluted 1:50 into 5 mL of fresh broth and incubated for 3 hours at37° C. Organisms were pelleted by centrifugation in a Beckmnan J-6Mcentrifuge for 5 minutes at 3000 rpm (1500 x g) and the pellets wereresuspended in 5 mL phosphate buffered saline (PBS) and the opticaldensity at 570 nm was determined. On the basis of the determination thatone OD unit equals 3×10⁷ colony forming units/mL, yeast cells werediluted to 2×10⁶ cells/mL in Sabouraud Dextrose broth.

Domain III peptides derived from or based on BPI to be screened wereoriginally constituted in Dulbecco's-PBS, were diluted to 100 μg/mL inbroth and were serially diluted 2-fold into wells of a 96 well sterile,flat bottom, non-pyrogenic tissue culture plate (Costar, Cambridge,Mass.). All assays were performed in triplicate. 2×10⁵ organisms wereadded at 100 μl per well; fmal volume was 200 μL/well; the plate wasincubated on a shaker at 37° C. for 18 hours; and the optical densitiesfor each well were read at 590 nm. FIG. 1 hereto graphically illustratesthe dose response curves for five peptides (MP.13, XMP.138, XMP.139,XMP.142 and XMP.143). All illustrated peptides reduced optical densityof the cultures to below 0.1 at doses of less than about 50 μg/mL, withXMP. 138 displaying the best results of the illustrated peptides at lowdosages. The broth assay data may be set out in terms of minimuminhibitory concentration (MIC), i.e. the lowest concentration requiredto reduce the optical density at 590 nm to below 0.1. The WC (μg/mL) ofeach of the five peptides listed above in FIG. 1 is 12.5, 3.13, 6.25,12.5 and 25.0, respectively.

In the radial diffusion assay procedures, the CA-1 cultures and peptidesolutions were prepared as in the broth assay procedure described above.Ten mL of molten underlayer agarose comprising 3% Sabouraud Dextrosebroth, 1% agarose (Pharmacia, Piscataway, N.J.), 0.02% Tween 20, and 10mM sodium phosphate at pH 7.4, was added to polystyrene tubes andmaintained in a 56° C. water bath until the addition of yeast. Tubeswere cooled to approximately 45° C., yeast were added to give a fmalconcentration of 1×10⁶ CFU/mL, and the tubes were mixed again byinverting. The contents were poured into level square petri dishes anddistributed evenly. The agarose solidified in less than 30 seconds andhad a uniform thickness of about 1 mm. A series of wells were punchedinto the hardened agarose using a sterile 3 mm punch attached to avacuum apparatus.

Peptides to be assayed were 2-fold serially diluted in Dulbecco's PBS(D-PBS) starting from a concentration of approximately 1 mg/ML. Five μLof each dilution were added to each well and the plates were incubatedat 37° C. for 3 hours. An overlayer of 10 mL of molten agarosecomprising 6% Sabouraud Dextrose broth, 1% agarose, and 10 mM sodiumphosphate, pH 7.4, (at approximately 45° C.) was then added and plateswere incubated overnight at 37° C. Following this overnight incubation,a dilute Coomassie solution was poured into the plates and allowed tostain for 24 hours.

Clear zones of growth inhibition around each well were measured withcalipers. The actual area of growth inhibition (mm² ) was calculated bysubtracting the area of the well. Table 1 below sets out the results ofthe radial diffusion assays for tested peptides in terms of the numberof picomoles (pmol) of peptide required to establish a 30 mm² area ofgrowth inhibition calculated by PROBIT analysis (e.g., calculated fromregression of the linear portion of log-concentration dose-responsecurve, log pmol/well vs. net area of inhibition).

                                      TABLE 1                                     __________________________________________________________________________                                     C. albicans                                    Peptide Peptide Amino HPLC % pmol/                                            (SEQ ID NO:) Acid Segment Purity 30 mm.sup.2 zone.sup.a                     __________________________________________________________________________    XMP.5 (1)                                                                             142-163             18   >2151                                          XMP.11 (2) 148-151, 153-161 76 645                                            XMP.12 (3) 141-169 26 >2099                                                   XMP.13 (4) 148-161 69 541                                                     XMP.13P.sup.f (4) 148-161 98 222                                              XMP.29 (5) (148-161) × 2 26 >1469                                       XMP.31 (6) 148-161, A @ 148 (K) 68 426                                        XMP.32 (7) 148-161, A @ 149 (S) 70 294                                        XMP.33 (8) 148-161, A @ 150 (K) 58 603                                        XMP.34 (9) 148-161, A @ 151 (V) 51 319                                        XMP.35 (10) 148-161, A @ 152 (G) 72 442                                       XMP.36 (11) 148-161, A @ 153 (W) 64 197                                       XMP.36 (11) 148-161, A @ 153 (W) 99 231                                       XMP.37 (12) 148-161, A @ 154 (L) 51 253                                       XMP.38 (13) 148-161, A @ 155 (I) 70 391                                       XMP.39 (14) 148-161, A @ 156 (Q) 53 1792                                      XMP.40 (15) 148-161, A @ 157 (L) 53 253                                       XMP.41 (16) 148-161, A @ 158 (F) 63 734                                       XMP.42 (17) 148-161, A @ 159 (H) 59 548                                       XMP.43 (18) 148-161, A @ 160 (K) 53 785                                       XMP.44 (19) 148-161, A @ 161 (K) 70 578                                       XMP.55 (20) 152-172 28 >2666                                                  XMP.82 (21) 148-161, W @ 158 (F) 58 518                                       XMP.83 (22) 148-161, β(1-naphthyl)-A 63 1804                              @ 153 (W)                                                                    XMP.85 (23) 148-161, L @ 152 (G) 74 >1881                                     XMP.86 (24) 148-161, L @ 156 (Q) 51 >2048                                     XMP.87 (25) 148-161, L @ 159 (H) 63 >1536                                     XMP.91 (26) 148-161, F @ 156 31 >3844                                          (Q)                                                                          XMP.92 (27) 148-161, K @ 156 (Q) 50 299                                       XMP.94 (28) 148-161, F @ 159 (H) 59 >923                                      XMP.95 (29) 148-161, F @ 152 (G) 57 >1398                                     XMP.96 (30) 148-161, F @ 161 (K) 60 1856                                      XMP.97 (31) 148-161, K @ 152 (G) 67 213                                       XMP.97P.sup.f (31) 148-161, K @ 152 (G) 98 303.5                              XMP.100 (32) 148-161, K @ 152 (G) & 61 462                                     156 (Q)                                                                      XMP.101 (33) (148-161) × 2[K @ 152(G) & 156(Q), 16 >1040                 F @ 159(H) & 161(K)]                                                         XMP.104 (34) 148-161, S @ 156 (Q) 34 >5569                                    XMP.106 (35) 148-161, T @ 156 (Q) 26 1032                                     XMP.107 (36) 148-161, W @ 159 (H) 55 >2796                                    XMP.108 (37) 148-161, W @ 161 (K) 50 >3219                                    XMP.109 (38) 148-161, β(1-naphthyl)-A 41 >2839                            @ 158 (F)                                                                    XMP.110 (39) 148-161, β(1-naphthyl)-A 56 >2922                            @ 159 (H)                                                                    XMP.111 (40) 148-161, β(1-naphthyl)-A 73 >2809                            @ 161 (K)                                                                    XMP.113 (41) 148-161, F @ 157 (L) 46 947                                      XMP.116 (42) 148-161, K @ 152 (G), β(1-naphthyl)-A 72 670                 @ 153 (W)                                                                    XMP.123 (43) 148-161, p-Amino-F @ 156 (Q) 64 1721                             XMP.124 (44) 148-161, K @ l52 (G), W @ 67 351                                  158 (F)                                                                      XMP.125 (45) 148-161, Y @ 156 (Q) 54 >3150                                    XMP.126 (46) 148-161, W.sub.D @ 153 (W) 54 1404                               XMP.127 (47) 148-161, F @ 153 (W) 63 226                                      XMP.127P.sup.f (47) 148-161, F @ 153 (W) 94 935                               XMP.128 (48) 148-161 F.sub.D @ 153 (W) 51 1179                                XMP.129 (49) 148-161, β(1-naphthyl)A.sub.D @ 28 2117                      153 (W)                                                                      XMP.130 (50) 148-161, β(2-naphthyl)A @ 80 1159                            153 (W)                                                                      XMP.131 (51) 148-161, β(2-naphthyl)A.sub.D @ 60 2493                      153 (W)                                                                      XMP.132 (52) 148-161, PYR @ 153 (W) 50 353                                    XMP.133 (53) 148-161, p-Amino-F @ 153 (W) 47 284                              XMP.134 (54) 148-161, p-Amino-F @ 152 (G) 68 1255                             XMP.135 (55) 148-161, K @ 153 (W) 70 428                                      XMP.137 (56) C-148-161-C 28 >2286                                             XMP.138 (57) 148-161, K @ 152 (G),F @ 153 (W) 61 257                          XMP.139 (58) 148-161, Y @ 153 (W) 60 323                                      XMP.142 (59) 148-161, W @ 157 (L) 57 1244                                     XMP.143 (60) 148-161, β(1-naphthyl)-A 65 >2839                            @ 157 (L)                                                                    XMP.144 (61) 148-161, Cyclohexyl-A 60 695                                      @ 153 (W)                                                                    XMP.146 (62) 148-161, β(1-naphthyl)-A @ 159 (H) & 53 .sup.b                                               161 (K)                                      XMP.148 (63) 148-l61, β(1-naphthyl)-A 62 >2805                            @ 153 (W) & 159 (H)                                                          XMP.161 (64) 148-161, K @ 152 (G) & A @ 75 >2999                               153 (W)                                                                      XMP.166 (65) 148-161, V @ 153 (W) 68 171                                      XMP.222 (66) 148-161 β(1-naphthyl)-A @ 153 (W) & 57 >2,610                                                161 (K)                                      XMP.222P.sup.f (66) 148-161 β(1-naphthyl)-A @ 153 (W) & >99 NT                                            161 (K)                                      XMP.223 (67) 148-161, β(1-naphthyI)-A @ 39 .sup.b                         153 (W) & 157 (L)                                                            XMP.224 (68) 148-161, β(1-naphthyl)-A @ 153, p-amino- 55 >2,443                                           F @ 156 (Q)                                  XMP.225 (69) 148-161, p-amino-F @ 152, β(1-naphthyl)- 77 >2,506                                           A @ 153 (W)                                  XMP.225P.sup.f (69) 148-161, p-amino-F @ 152, β(1-naphthyl)- >99                                        >2,736                                          A @ 153 (W)                                                                  XMP.226 (70) 148-161, β(1-naphthyl)-A @ 153, W @ 50 >2,597                                                158 (F)                                      XMP.226P.sup.f (70) 148-161, β(1-naphthyl)-A @ 153, W @ 97 >2,895                                         158 (F)                                      XMP.227 (71) 148-161, β(1-naphthyl)-A @ 157 (L) & 54 >2,365                                               161 (K)                                      XMP.228 (72) 148-161, p-amino-F @ 156 (Q), β(1- 43 .sup.b                 naphthyl)-A @ 161 (K)                                                        XMP.229 (73) 148-161, p-amino-P @ 152 (G), β(1- 81 .sup.b                 naphthyl)-A @ 161 (K)                                                        XMP.230 (74) 148-161, W @ 158 (F), β(1-naphthyl)-A @ 51 >2,386                                            161 (K)                                      XMP.231 (75) 148-161, β(1-naphthyl)-A @ 157 (L) & 44 .sup.b                                               159 (H)                                      XMP.232 (76) 148-161, p-amino-F @ 156 (Q), β(1- 28 .sup.b                 naphthyl)-A @ 159 (H)                                                        XMP.233 (77) 148-161, p-amino-F @ 152 (G), β(1- 53 .sup.b                 naphthyl)-A @ 159 (H)                                                        XMP.234 (78) 148-161, W @ 158 (F), β(1-naphthyl)-A @ 26 .sup.b                                            159 (H)                                      XMP.235 (79) 148-161, p-amino-F @ 156 (Q), β(1- 30 .sup.b                 naphthyl)-A @ 157 (L)                                                        XMP.236 (80) 148-161, p-amino-F @ 152 (G), β(1- 73 >2,631                 naphthyl)-A @ 157 (L)                                                        XMP.237 (81) 148-161, β(1-naphthyl)-A @ 157 (L), W 34 >2,777                                              @ 158 (F)                                    XMP.238 (82) 148-161, p-amino-F @ 152 (G) & 156 (Q) 66 2,702                  XMP.239 (83) 148-161, p-amino-F @ 156 (Q), W @ 158 30 >2,802                   (F)                                                                          XMP.240 (84) 148-161, p-amino-P @ 152 (G), W @ 158 55 >2,802                   (F)                                                                          XMP.241 (85) 148-161, L @ 156 (Q), W @ 158 (F) 55 >2,161                      XMP.242 (86) 148-161, β(2-naphthyl)A.sub.D @ 153 (W), L 52 359                                            @ 156 (Q)                                    XMP.243 (87) 148-161, β(2-naphthyl)A.sub.D @ 153 (W), W Mixture                                         716                                             @ 158 (F)                                                                    XMP.244 (88) 148-161, β(2-naphthyl)A.sub.D @ 153 (W), L 43 859                                            @ 156 (Q), W @                                158 (F)                                                                      XMP.249 (89) 148-161, G @ 153 (W) 46 1,242                                    XMP.250 (90) 148-161, L @ 153 (W) 33 536                                      XMP.251 (91) 148-161, I @ 153 (W) 44 1,289                                    XMP.252 (92) 148-161, A.sub.D @ 153 (W) 52 1,613                              XMP.253 (93) 148-161, V.sub.D @ 153 (W) 51 1,108                              XMP.254 (94) 148-161, β-A @ 153 (W) 68 1,040                             XMP.255 (95) 148-161, α-Aminobutyric Acid @ 153 (W) 44 392                                              XMP.255P.sup.f (95) 148-161, α-Ami                                     nobutyric Acid @ 153 (W) 94 NT                 XMP.256 (96) 148-161, γ-Aminobutyric Acid @ 153 (W) 38 .sup.b                                           XMP.257 (97) 148-161, α-Methyl-A                                       @ 44 1,321                                      153 (W)                                                                      XMP.258 (98) 148-161, t-Butyl-G @ 153 (W) 62 880                              XMP.259 (99) 148-161, N-Methyl-G @ 153 (W) 88 2,117                           XMP.260 (100) 148-161, N-Methyl-V @ 153 (W) 75 742                            XMP.261 (101) 148-161, N-Methyl-L @ 153 (W) 85 867                            XMP.262 (102) 148-161, N @ 156 (Q) 68 984                                     XMP.263 (103) 148-161, E @ 156 (Q) 49 1,197                                   XMP.264 (104) 148-161, D @ 156 (Q) 60 879                                     XMP.265 (105) 148-161, R @ 156 (Q) 42 2,996                                   XMP.266 (106) 148-161, K @ 152 (G), V @ 153 (W) 52 984                        XMP.267 (107) 148-161, K @ 152 (G), A @ 58 256                                 154 (L)                                                                      XMP.267P.sup.f (107) 148-161, K @ 152 (G), A @ 97 106                          154 (L)                                                                      XMP.268 (l08) 148-161, V @ 153 (W), A @ 154 (L) 62 308                        XMP.268P.sup.f (108) 148-l61, V @ 153 (W), A @ 154 (L) 95 63                  XMP.269 (109) 148-161, K @ 152 (G), V @ 153 (W), A 30 635                      154 (L)                                                                      XMP.270 (110) (148-161) + (148-161), L @ 1st 156 (Q) 31 >722                  XMP.271 (111) (148-161) + (148-161), L @ 2nd 156 (Q) 31 >1,995                XMP.272 (112) (148-161) + (148-161), L @ both 156 (Q) 32 >2,599                                               XMP.273 (113) (148-161) + (148-161), F                                       @ 1st 156 (Q) 59 >2,120                        XMP.274 (114) (148-161) + (148-161), F @ 2nd 156 (Q) 40 >2,457                XMP.275 (115) (148-161) + (148-161), F @ both 156 (Q) 34 .sup.b                                               XMP.283 (116) 148-161, K @ 152 (G), F @                                      153 (W), K 36 1,336                             @ 156 (Q)                                                                    XMP.284 (117) 149-161, K @ 152 (G) 60 1,460                                   XMP.284P.sup.f (117) 149-161, K @ 152 (G) 96 373                              XMP.285 (118) 149-160, K @ 152 (G) 75 >3,024                                  XMP.286 (119) 150-161, K @ 152 (G) 61 1,216                                   XMP.286P.sup.f (119) 150-161, K @ 152 (G) 80 253                              XMP.287 (120) 149-159, K @ 152 (G) 58 >3,509                                  XMP.288 (121) 150-160, K @ 152 (G) 78 >3,062                                  XMP.288P.sup.f (121) 150-160, K @ 152 (G) 94 279                              XMP.289 (122) 151-161, K @ 152 (G) 78 1,542                                   XMP.289P.sup.f (122) 151-161, K @ 152 (G) 94 658                              XMP.290 (123) 149-158, K @ 152 (G) 79 >2,233                                  XMP.291 (124) 150-159, K @ 152 (G) 55 >5,039                                  XMP.292 (125) 151-160, K @ 152 (G) 78 >4,463                                  XMP.293 (126) 152-161, K @ 152 (G) 78 1,156                                   XMP.293P.sup.f (126) 152-161, K @ 152 (G) 95 215                              XMP.294 (127) 149-157, K @ 152 (G) 63 >4,634                                  XMP.295 (128) 150-158, K @ 152 (G) 82 >1,977                                  XMP.295P.sup.f (128) 150-158, K @ 152 (G) 98 >2,612                           XMP.296 (129) 151-159, K @ 152 (G) 64 >5,573                                  XMP.297 (130) 152-160 K @ 152 (G) 81 1,817                                    XMP.297P.sup.f (130) 152-160 K @ 152 (G) 97 564                               XMP.298 (131) 153-161 84 2,628                                                XMP.298P.sup.f (131) 153-161 95 1,106                                         XMP.299 (132) 149-156, K @ 152 (G) 68 >8,768                                  XMP.300 (133) 150-157, K @ 152 (G) 75 1,957                                   XMP.300P.sup.f (133) 150-157, K @ 152 (G) 97 993                              XMP.301 (134) 151-158, K @ 152 (G) 41 .sup.b                                  XMP.302 (135) 152-159, K @ 152 (G) 75 >5,497                                  XMP.302P.sup.f (135) 152-159, K @ 152 (G) 98 2,070                            XMP.303 (l36) 153-160 78 >4,694                                               XMP.303P.sup.f (136) 153-160 98 1,307                                         XMP.304 (137) 154-161 84 >8,290                                               XMP.305 (138) 149-155, K @ 152 (G) 73 >10,228                                 XMP.306 (139) 150-156, K @ 152 (G) 62 >10,485                                 XMP.307 (140) 151-157, K @ 152 (G) 67 >8,345                                  XMP.308 (141) 152-158, K @ 152 (G) 72 .sup.b                                  XMP.309 (142) 153-159 76 .sup.b                                               XMP.310 (143) 154-160 56 >9,475                                               XMP.311 (144) 155-161 77 .sup.b                                               XMP.312 (l45) 149-154, K @ 152 (G) 76 >11,120                                 XMP.313 (146) 150-155, K @ 152 (G) 59 >11,050                                 XMP.314 (147) 151-156, K @ 152 (G) 73 >13,497                                 XMP.315 (148) 152-157, K @ 152 (G) 84 >5,069                                  XMP.315P.sup.f (148) 152-157, K @ 152 (G) 94 >12,853                          XMP.316 (149) 153-158 85 .sup.h                                               XMP.316P.sup.f (149) 153-158 98 .sup.g                                        XMP.317 (150) 154-159 64 .sup.b                                               XMP.318 (151) 155-160 84 .sup.b                                               XMP.319 (152) 156-161 73 .sup.b                                               XMP.320 (153) 153-157 63 >4,055                                               XMP.321 (154) 153-157-K 66 >5,851                                             XMP.322 (155) 153-157-K-K 69 3,488                                            XMP.323 (156) K-153-157-K 63 >4,627                                           XMP.324 (157) K-153-157-K-K 67 894                                            XMP.325 (158) K-K-153-157 66 4,135                                            XMP.326 (159) K-K-153-157-K 59 2,182                                          XMP.327 (160) K-K-153-157-K-K 75 353                                          XMP.327P.sup.f (160) K-K-153-157-K-K 94 630                                   XMP.330 (161) 153-156 95 .sup.b                                               XMP.331 (162) †K-K-153-157-K-K 66 .sup.b                               XMP.331P.sup.f (162) †K-K-153-157-K-K 97 >3,493                        XMP.332 (163) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D                                           -W.sub.D -K.sub.D -K.sub.D 64 356                                              XMP.332P.sup.f (163) K.sub.D -K.sub.D                                        -L.sub.D -Q.sub.D -I.sub.D -L.sub.D                                           -W.sub.D -K.sub.D -K.sub.D 98 338                                              XMP.333 (164) K.sub.D -K-153-157-K-K 62                                      673                                            XMP.333P.sup.f (164) K.sub.D -K-153-157-K-K 98 361                            XMP.334 (165) P.sub.D -K-153-157-K-K 67 1,449                                 XMP.334P.sup.f (165) P.sub.D -K-153-157-K-K 89 1,065                          XMP.335 (166) P-K-153-157-K-K 61 871                                          XMP.335P.sup.f (166) P-K-153-157-K-K 98 1,353                                 XMP.336 (167) R-R-153-157-R-R 22 >7,332                                       XMP.336P.sup.f (167) R-R-153-157-R-R 97 .sup.h                                XMP.337 (168) H-H-153-157-H-H 70 .sup.b                                       XMP.337P.sup.f (168) H-H-153-157-H-H 94 >3,350                                XMP.338 (169) ORN-ORN-153-157-ORN-ORN 74 1,194                                XMP.338P.sup.f (169) ORN-ORN-153-157-ORN-ORN 96 1,011                         XMP.339 (170) DAB-DAB-153-157-DAB-DAB 74 2,878                                XMP.339P.sup.f (170) DAB-DAB-153-157-DAB-DAB 98 2,599                         XMP.340 (171) p-amino-F-p-amino-F-153-157-p- 66 .sup.b                         amino-F-p-amino-F                                                            XMP.340P.sup.f (171) p-amino-F-p-amino-F-153-157-p- 94 .sup.b                  amino-F-p-amino-F                                                            XMP.341 (172) PYR-PYR-153-157-PYR-PYR 76 .sup.b                               XMP.341P.sup.f (172) PYR-PYR-153-157-PYR-PYR 99 .sup.b                        XMP.342 (173) K.sub.D -K.sub.D -153-157-K.sub.D -K.sub.D 72 1,591                                             XMP.342P.sup.f (173) K.sub.D -K.sub.D                                        -153-157-K.sub.D -K.sub.D 97 700                                               XMP.343 (174) K-K-153-157-K-K, V @ 153                                       (K) 69 NT                                      XMp.343P.sup.f (174) K-K-153-157-K-K, V @ 153 (W)  245                        XMP.344 (175) K-K-153-157-K-K, A @ 154 (L) 71 NT                              XMP.344P.sup.f (175) K-K-153-157-K-K, A @ 154 (L) 96 251                      XMP.345 (176) K-K-153-157-K-K, A @ 157 (L) 72 NT                              XMP.345P.sup.f (176) K-K- 153-157-K-K, A @ 157 (L) 93 l,211                   XMP.346 (177) K-K-153-157-K-K, p-Amino-F @ 90 NT                               153 (W)                                                                      XMP.346P.sup.f (177) K-K-153-157-K-K, p-Amino-F @ 98 640                       153 (W)                                                                      XMP.347 (178) K-K-153-157-K-K, β(2-naphthyl) 54 NT                        A.sub.D @ 153 (W), L @ 156 (Q)                                               XMP.347P.sup.f (178) K-K-153-157-K-K, β(2-naphthyl) 97 391                                                A.sub.D @ 153 (W), L @ 156 (Q)                                               XMP.348 (179) K-K-K-153-157-K-K 69 NT                                         XMP.348P.sup.f (179) K-K-K-153-157-K-K                                       97 284                                         XMP.349 (180) K-K-153-157-K-K-K 67 NT                                         XMP.349P.sup.f (180) K-K-153-157-K-K-K 98 120                                 XMP.350 (181) K-K-K-153-157-K-K-K 65 NT                                       XMP.350P.sup.f (181) K-K-K-153-157-K-K-K 98 129                               XMP.351 (182) K-K-153-158-K-K 59 NT                                           XMP.351P.sup.f (182) K-K-153-158-K-K 98 385                                   XMP.352 (183) K-K-153-161 66 NT                                               XMP.352P.sup.f (183) K-K-153-161 98 354                                       XMP.353 (184) P-153-161* 66 3,093                                             XMP.353P.sup.f (184) P-153-161* 99 463                                        XMP.354 (185) †P-153-161* 72 NT                                        XMP.354P.sup.f (185) †P-153-161* >99 6,361                             XMP.355 (186) P-153-161 74 2,529                                              XMP.355P.sup.f (186) P-153-161 99 218                                         XMP.356 (187) †P-153-161 58 NT                                         XMP.356P.sup.f (187) †P-153-161 >99 550                                XMP.357 (188) K-153-160-P 64 NT                                               XMP.357P.sup.f (188) K-153-160-P 98 204                                       XMP.358 (189) K-K-153-160-P 61 NT                                             XMP.358P.sup.f (189) K-K-153-160-P 98 550                                     XMP.359 (190) C.sub.D -153-161 83 NT                                          XMP.359P.sup.f (190) C.sub.D -153-161 96 .sup.b                               XMP.360 (191) K.sub.D -C.sub.D -154-158-C-K.sub.D  NT                         XMP.361 (192) K.sub.D -C-154-158-C-K.sub.D 40 NT                              XMP.361P.sup.f (192) K.sub.D -C-154-158-C-K.sub.D 96 NT                       XMP.362 (193) K.sub.D -K-C-154-158-C-K-K.sub.D 37 NT                          XMP.362P.sup.f (193) K.sub.D -K-C-154-158-C-K-K.sub.D 98 NT                   XMP.363 (194) K.sub.D -W.sub.D -154-159-K.sub.D -K.sub.D 75 1,015                                             XMP.363P.sup.f (194) K.sub.D -W.sub.D                                        -154-159-K.sub.D -K.sub.D 97 741                                               XMP.364 (195) †K.sub.D -W.sub.D                                       -154-159-K.sub.D -K.sub.D 62 NT                XMP.364P.sup.f (195) †K.sub.D -W.sub.D -154-159-K.sub.D -K.sub.D                                      98 1,523                                       XMP.365 (196) K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D -L.sub.D                                           -F.sub.D -H.sub.D -K.sub.D - 66 1,294                                           K.sub.D                                      XMP.365P.sup.f (196) K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D                                             -L.sub.D -F.sub.D -H.sub.D -K.sub.D - 97                                      489                                             K.sub.D                                                                      XMP.366 (197) †K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D                                            -L.sub.D -F.sub.D -H.sub.D - 65 NT                                              K.sub.D -K.sub.D                             XMP.366P.sup.f (197) †K.sub.D -W.sub.D -L.sub.D -I.sub.D                                              -Q.sub.D -L.sub.D -F.sub.D -H.sub.D - 99                                      725                                             K.sub.D -K.sub.D                                                             XMP.367 (198) K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D -Q.sub.D                                           -I.sub.D -L.sub.D -W.sub.D - 69 4,641                                           K.sub.D                                      XMP.367P.sup.f (198) K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D                                             -Q.sub.D -I.sub.D -L.sub.D -W.sub.D - 99                                      1,108                                           K.sub.D                                                                      XMP.368 (199) †K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D                                            -Q.sub.D -I.sub.D -L.sub.D - 74 NT                                              W.sub.D -K.sub.D                             XMP.368P.sup.f (199) †K.sub.D -K.sub.D -H.sub.D -F.sub.D                                              -L.sub.D -Q.sub.D -I.sub.D -L.sub.D - 93                                      744                                             W.sub.D -K.sub.D                                                             XMP.369 (200) 152-161, K @ 152 (G), ORN @ 156 (Q) 60 993                      XMP.369P.sup.f (200) 152-161, K @ 152 (G), ORN @ 156 (Q) 95 877                                               XMP.370 (201) †152-161, K @ 152                                       (G), ORN @ 156 (Q) 59 NT                       XMP.370P.sup.f (201) †152-161, K @ 152 (G), ORN @ 156 (Q) >99                                         310                                            XMP.371 (202) 152-161, K @ 152 (G), DAB @ 156 (Q) 74 843                      XMP.371P.sup.f (202) 152-161, K @ 152 (G), DAB @ 156 (Q) 97 523                                               XMP.372 (203) †152-161, K @ 152                                       (G), DAB @ 156 (Q) 50 NT                       XMP.372P.sup.f (203) †152-161, K @ 152 (G), DAB @ 156 (Q) 99 328       XMP.373P.sup.f (204) †152-161, K @ 152 (G) 98 298                      XMP.374 (205) K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D -W.sub.D                                           -K.sub.D -K.sub.D                              XMP.374P.sup.f (205) K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D                                             -W.sub.D -K.sub.D -K.sub.D 97 198                                              XMP.375P.sup.f (206) K.sub.D -K.sub.D                                        -W.sub.D -A.sub.D -I.sub.D -Q.sub.D                                           -L.sub.D -K.sub.D - 95 123                      K.sub.D                                                                      XMP.376P.sup.f (207) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D                                             -A.sub.D -W.sub.D -K.sub.D -K.sub.D 92                                        138                                            XMP.377P.sup.f (208) K-K-K-W-A-I-Q-L-K-K 97 146                               XMP.378P.sup.f (209) P-W-A-I-Q-L-K-K 97 2,084                                 XMP.379P.sup.f (210) K-K-P-W-A-I-Q-L-K-K 98 547                               XMP.380P.sup.f (211) K-K-Q-L-L-L-L-K-K 99 886                                 XMP.381P.sup.f (212) K-K-L-Q-L-L-L-K-K 99 391                                 XMP.382P.sup.f (213) K-K-L-L-Q-L-L-K-K 99 1,437                               XMP.383P.sup.f (214) K-K-L-L-L-Q-L-K-K 99 473                                 XMP.384P.sup.f (215) K-K-L-L-L-L-Q-K-K 99 2,804                               XMP.385P.sup.f (216) K-K-L-L-L-L-L-K-K 99 127                                 XMP.386P.sup.f (217) 152-161, K @ 152 (G), A @ 154 (L) 97 113                 XMP.387P.sup.f (218) 152-161, P @ 152 (G), A @ 154 (L) 93 82                  XMP.388P.sup.f (219) 152-161 97 170                                           XMP.389P.sup.f (220) 151-161, K @ 151 (V) 99 206                              XMP.390P.sup.f (221) 151-161, K @ 151 (V), P @ 152 (G) 98 674                 XMP.391P.sup.f (222) 150-161 97 68                                            XMP.392P.sup.f (223) 150-161, P @ 152 (G) 98 569                              XMP.393 (224) 148-161, P @ 152 (G) >99 NT                                     XMP.394 (225) K.sub.D -L.sub.D -F.sub.D -R.sub.D -β(1-naphthyl)A.su                                     b.D -Q.sub.D -  NT                              A.sub.D -K.sub.D -β(1-naphthyl)A.sub.D -K.sub.D -G.sub.D -S.sub.D                                      -                                               I.sub.D -K.sub.D -I.sub.D                                                    XMP.395 (226) 148-161, β(1-naphthyl)A @ 153 (W), L  NT                    @ 156 (Q)                                                                    XMP.396 (227) 148-161, β(1-naphthyl)A @ 153 (W), F @  NT                  156 (Q)                                                                      XMP.397 (228) 148-161, p-amino-F @ 152 (G), β(1-  NT                      naphthyl)A @ 153 (W), W @ 158 (F)                                            XMP.398 (229) 148-161, L @ 156 (Q), β(1-naphthyl)A @  NT                  157 (L)                                                                      XMP.399 (230) 148-161, F @ 156 (Q), W @ 158 (F)  NT                           XMP.400 (231) 148-161, β(1-naphthyl)A @ 153 (W), L @  NT                  156, W @ 158                                                                 XMP.401 (232) 148-161, F @ 156 (Q), β(1-naphthyl)A @  NT                  157 (L)                                                                      XMP.402 (233) 148-161, β(1-naphthyl)A @ 153 (W), F @  NT                  156 (Q), W @ 158 (F)                                                         XMP.403 (234) 148-161, β(1-naphthyl)A @ 153 (W) and  NT                   157 (L), W @ 158 (F)                                                         XMP.404 (235) 148-161, F @ 156 (Q), β(1-naphthyl)A @  NT                  157 (L), W @ 158 (F)                                                         XMP.405 (236) 148-161, L @ 156 (Q), β(1-naphthyl)A @  NT                  157 (L), W @ 158 (F)                                                         XMP.406P.sup.f (237) 147-161, P @ 147 (S), A @ 153 (W) 99 423                 XMP.407P.sup.f (238) 147-162, P @ 147 (S), A @ 153 (W), D 96 1,240                                             @ 162 (I)                                    XMP.408P.sup.f (239) L-K-K-K-W-A-I-Q (cyclized  .sup.b                         head to tail)                                                                XMP.409P.sup.f (240) S-K-153-157-K-K, A @ 154 (L) 98 795                      XMP.410P.sup.f (241) CH.sub.3 --(CH.sub.2).sub.6 --CO-XMP.344 95 599                                          XMP.411 (242) CH.sub.3 --(CH.sub.2).sub.                                     10 --CO-XMP.344                                XMP.412 (243) L-K-K-K-W-A-I-Q  NT                                             XMP.414 (244) CH.sub.3 --(CH.sub.2).sub.6 --CO-XMP.365                        XMP.415 (245) CH.sub.3 --(CH.sub.2).sub.10 --CO-XMP.365                       XMP.416 (246) NH.sub.2 --(CH.sub.2).sub.7 --CO-XMP.365                        XMP.417 (247) NH.sub.2 --(CH.sub.2).sub.11 --CO-XMP.365                       XMP.418 (248) 148-150, 152-161, P @ 152 (G)  572                              XMP.419 (249) †K.sub.D -W.sub.D -L.sub.D -I.sub.D -L.sub.D                                            -P.sub.D -H.sub.D -K.sub.D -  NT                                                K.sub.D                                      XMP.420 (250) Fmoc-K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D -L.sub.D                                      -F.sub.D -  NT                                  H.sub.D -K.sub.D -K.sub.D                                                  __________________________________________________________________________     .sup.a pmoles of peptide added to well to achieve a 30 mm.sup.2 zone as       determined by PROBIT analysis                                                 .sup.b No detectable activity up to 5 μg/well                              .sup.c NT = not tested                                                        .sup.d †= peptide has an acetylated amino terminus;                    *= peptide has a nonamidated carboxyterminus                                  .sup.e Abbreviations: X.sub.D refers to a Damino acid; ORN is ornithine;      DAB is diamino butyric acid; PYR is pyridinylalanine (free acid)              .sup.f "P" refers to XMP peptide purified as described in Example 1           .sup.g inactive to 7,194 pmol                                                 .sup.h inactive to 5,268 pmol                                            

EXAMPLE 3 In Vitro and In Vivo Effect of Anti-Fungal Peptides on aVariety of Fungal Species

This example addresses in vitro and in vivo screening of various DomainIII derived peptides for anti-fungal activity against a number of fungalspecies, including Candida species and strains resistant to variousanti-fungal agents, in a radial diffusion assay. The example alsoaddresses the effects of combinations of peptide and amphotericin Bagainst Candida strain SLU-1.

Domain III derived peptides were tested for their fungicidal activity onamphotericin resistant Candida. Resistant colonies of Candida wereisolated using a gradient plate technique. A slanted Sabouraud dextroseagar plate was poured and allowed to harden. The plate was made leveland additional agar supplemented with nystatin (Sigma, St. Louis, Mo.,cat. no. N-3503) at a concentration of 10 p,g/mL was poured. Cells fromthe the CA-1 colony of Candida albicans SLU-1 strain described inExample 2 (10⁷ cells in a volume of 100 μL) were spread over the plateand incubated at 37° C. overnight. Initially, minute colonies were seenand required additional incubation time to achieve the size of wildtypecolonies. Eleven colonies were designated SLU-2A though SLU-2K. Thesecolonies were serially passaged in Sabouraud dextrose broth supplementedwith increasing concentrations of amphotericin B, after an initialpassage with 2 μg/mL amphotericin B. After the fmal passage in 20 zg/mLamphotericin B, colonies 2G, 2H, 2J and 2K remained viable whereas thewildtype SLU-1 strain remained sensitive to 1 pg/mL amphotericin B. Noneof the resistant strains demonstrated germ tube formation in fetalbovine serum. In addition, these isolates had a much slower growth ratethan SLU-1 and did not form hyphae at 3TC.

For the radial diffusion assays, Candida albicans SLU-1 were grown asdescribed above and SLU-2G were grown overnight in Sabouraud dextrosebroth supplemented with 10 μg/mL amphotericin B and 5 μg/mL cefiriaxoneat 37° C. Cultures were diluted 1:25 into fresh, unsupplemented brothand allowed to grow for 5 hours at 37° C. Cells were pelleted at 1,500 Xg for 5 minutes at 4 ° C. Supernatant was decanted and replaced with 5mL of 10 mM phosphate buffer, pH 7.4. After centrifugation the cellpellets were resuspended with 5 mL phosphate buffer for an OD₅₇₀determination. One OD₅₇₀ for SLU-1 cells was 3×10° CFU/mL and for SLU-2Gcells was 5×10⁶ CFU/mL.

Cells were added to 10 mL of molten, cooled (˜45° C.) underlayer agaroseto a concentration of 1×10⁶ /mL and the suspension was poured into alevel square petri plate with gentle rocking to allow evena-distribution and solidification to a uniform thickness of about 1 mm.Wells were cut into the hardened agarose with a sterilized, 3 mmdiameter punch with vacuum.

Peptides were two-fold serially diluted with D-PBS from a startingconcentration of approximately 1 mg/mL. Amphotericin B and nystatin weresimilarly diluted starting at 100 and 225 μg/mL, respectively. Five μLwere added per well and allowed to diffuse at 37° C. for 1.5-2.0 hours.Then 10 mL of molten overlayer agarose were added and the plates wereincubated inverted at 37° C. overnight. Plates were stained with adilute Coomassie solution, inhibition zones were measured with calipersand net areas were calculated, then converted to pmol values by PROBrITanalysis. The results of a representative experiment are shown in FIG.2A for the SLU-1 strain and FIG. 2B for the SLU-2G strain. In FIGS. 2Aand 2B, the fungicidal activity is represented for XMP. 13 as opencircles; for XMP.37 as closed circles; for XMP.97 as open triangles; forXMP.127 as closed triangles; for amphotericin B as open squares; and fornystatin as closed squares. The pmol for a 30 mm² zone of inhibitionwere calculated to be: for XMP. 13, 689 pmol against SLU-1 and 129 pmolagainst SLU-2G; for XMP.37, 231 pmol against SLU-1 and 75 pmol againstSLU-2G; for XMP.97, 670 pmol against SLU-1 and 161 pmol against SLU-2G;for XMP.127, 935 pmol against SLU-1 and 116 pmol against SLU-2G; foramphotericin B, 36 pmol against SLU-1 and >541 pmol for SLU-2G; and fornystatin, 98 pmol against SLU-1 and >1,215 pmol against SLU-2G. As shownin FIGS. 2A and 2B, representative Domain Im derived peptides XMP.13,XMP.37, XMP.97 and XMP.127 demonstrated fungicidal activity against boththe SLU-1 wild type strain and the SLU-2G amphotericin B-resistantstrain, with better activity demonstrated against the SLU-2Gamphotericin B resistant strain. In contrast, amphotericin B waseffective against the original SLU-1 strain but did not kill the SLU-2Gresistant cells. These results demonstrate that Domain III derivedpeptides according to the invention are effective fungicidal agents by amechanism different from that of amphotericin B.

Further experiments were performed to determine the anti-fungal activityof Domain III derived peptides on commercially-available strains ofCandida considered resistant to other anti-fungal agents:polyene-resistant C. albicans (ATCC Accession No. 38247),5-fluorocytosine-resistant C. albicans (ATCC No. 44373), azole-resistantC. albicans (ATCC No. 62342), and ketoconazole-resistant C. abicans(ATCC No. 64124). Fungicidal activity of representative peptides XMP.13,XMP.36, XMP.97, XMP.127, and XMP.166 was not reduced on the abovestrains tested, indicating that the peptides are effective by amechanism different than that of the other anti-fungal agents.

The anti-fungal activity of Domain III derived peptides was alsoevaluated in vitro against a variety of fungal species, including Candiaglabrata, Candida krusei, Candida lusitaniae, Candida parapsilosis, andCandida tropicalis. For these experiments, one colony of each of theabove-listed Condida strains was picked from a Sabouraud's dextrose agar(SDA) plate and inoculated into 5 mL of Sabouraud's dextrose broth (SDB,2% dextrose and 1% neopeptone) or, for C. krusei, Yeast Malt broth (YM,Becton Dickenson, Cockeysville, Md., cat no. BLI 1405) in 12 mLpolyproplyene snap-cap tubes. The tube cultures were incubated overnightwith shaking at 37° C.

Cultures were harvested when the OD₅₇₀ of a 1:10 dilution was greaterthan or equal to the following values: 0.083 for Candida glabrata, 0.154for Candida krusei, 0.117 for Candida lusitaniae, 0.076 for Candidaparapsilosis, and 0.192 for Candida tropicalis. Cells were centrifugedfor 7 minutes in an Eppendorf microfuge at 3,000 rpm (about 1,500 g).The cell pellet was resuspended in 1 mL PBS and approximately 1×10⁷cells in about 0.5 mL were added to 10 mL of cooled underlay agar (3%SBD, 1% agarose, 0.02% Tween 20, 10 mM sodium phosphate buffer, pH 7.4at about 45° C.). The suspension was poured into square petri plates,allowed to solidify, and wells cut as decribed above.

Peptides were two-fold serially diluted with D-PBS from about 20 μL of astarting concentration of approximately 1 mg/mL. Five μL of peptidedilution were added per well and allowed to diffuse for at least about30 minutes into the agar at 37° C. (to allow complete diffusion). Then10 mL of molten overlayer agarose (6% SDB, 1% agarose, 10 mM sodiumphosphate buffer, pH 7.4 at about 45° C.) were added and the plates wereincubated inverted at 37° C. overnight. Plates were stained with adilute Coomassie solution, inhibition zones were measured with calipersand net areas were calculated, then converted to pmole values by PROBITanalysis. The results of a representative experiment are shown in Table2. Exemplary Domain III derived peptides XMP.13P, XMP.97P, XMP.127P,XMP.166P, XMP.286P, XMP.327P, XMP.331P, XMP.332P, XMP.333P and XMP.337Pdemonstrated some fungicidal activity against at least several of theCanida strains tested. These results demonstrate that Domain III denvedpeptides according to the invention are effective fungicidal agents in abroad spectrum against a variety of Candida species.

                                      TABLE 2                                     __________________________________________________________________________    Anti-fungal activity: pmol/30 mm.sup.2 zone.sup.a,d                                   Candida                                                                            Candida                                                                            Candida                                                                            Candida                                                                            Candida                                                                             Candida                                       albicans glabrata krusei lusitaniae parapsilosis tropicalis                 __________________________________________________________________________    XMP.13P.sup.c                                                                         2,233                                                                              1,022                                                                              1,747                                                                              746  1,502 452                                           XMP.97P.sup.c 2,019 1,786 907 900 868 193                                     XMP.127P 2,144 779 878 551 711 373                                            XMP.166 >3,079 2,100 3,240 1,133 1,199 864                                    XMP.286P.sup.c NT.sup.c 1,843 1,558 1,235 1,134 606                           Amphotericin B 11 <17 120 35 91 108                                           XMP.327P.sup.c 5,108 >6,295 3,327 120 119 2,598                               XMP.331P.sup.c b b >5,467 1,500 1,451 b                                       XMP.332P.sup.c 3,931 2,190 2,802 <219 170 866                                 XMP.333P.sup.c 5,191 4,040 4,101 174 209 2,894                                XMP.337P.sup.c b b 5,339 6,928 b b                                          __________________________________________________________________________     .sup.a pmol of peptide added to well to achieve a 30 mm.sup.2 zone as         determined by PROBIT analysis                                                 .sup.b No detectable activity up to 5 μg/well                              .sup.c NT = not tested                                                        .sup.d Actual pmol values obtained are dependent on assay conditions;         values in this Table for C. albicans higher than those presented in Table     1 due to higher effective concentration of agarose during incubation          .sup.e "P" refers to XMP peptide purified as described in Example 1      

The anti-fungal activity of Domain III derived peptides was evaluatedagainst a variety of fungal species, including species of Candida,Cryptococcus, Fusanium, Tnichophytonz, and Aspergillus, by an additionalassay protocol utilizing Alamar Blue. Alamar Blue is an indicator dyeformulated to measure quantitatively the proliferation of a variety ofhuman or animal cells, bacteria, or fungi. It consists of anoxidation-reduction (REDOX) indicator that yields a colorimetric changein response to metabolic activity.

For these experiments, species of Candida and Cryptococcus were grown inSabouraud's dextrose broth (SDB) overnight. Strains of filamentous fungi(Aspergillus, Fusanuwm, Tnichophyton) were obtained by irrigation of aconfluent culture from a petri dish. Cells were washed and adjusted to aconcentration of 5.0×10³ /mL in fresh SDB. Peptides were two-foldserially diluted in SDB from a concentration of 20 μg/mL. Controlsincluded amphotericin B, fluconazole, ketoconazole and griseofulvin.Antifungal drugs were also diluted in the same manner.

Assays were performned in 96-well microtiter plates. Peptides were in avolume of 100 μL per well followed by the addition of 100 μL of thefungal cell suspension. Final concentration of fungi was 2.5×10³ /mL andtest antifungal compounds started from a concentration of 10 μg/mnL.Almar Blue was added at 20 μL per well and plates were incubated for aperiod of 18 hours at 37° C. for Aspergillus, Candida, Cryptococcus,48-72 hours at 30° C. for slower growing fungi (i.e., Tiichophyton).Plates were centrifuged briefly (1,000 rpm, I minute) to pellet fungalcells or debris. 100 μL from each well was transferred to new 96-wellplates and an OD-,go reading was performed on an BUISA plate reader.

50μL from the original 96-well plates were plated on Sabouraud'sdextrose agar to determine fuingicidal activity. The wells to be platedwere deterniined by OD₅₉₀ readings. The lowest concentration of peptidewhich maintained the blue color (or OD reading) of the blank was chosenalong with the next two higher concentrations. Plates were allowed togrow for 18-48 hours depending on the rate of growth of each fungus.Minimal fungicidal activity (MIC) was determined as a 99.9% killing ofthe starting inoculum. For filamentous fungi, this was determined as thelowest concentration of peptide which showed no growth (completesterilization). The results of these assays are shown for representativepeptides in Tables 3 and 4. These results demonstrate that Domain IIIderived peptides according to the invention are effective fungicidalagents in a broad spectrum against a variety of fungal species.

                                      TABLE 3                                     __________________________________________________________________________    Antifungal Agent                                                                Minimum Fungicidal Concentration (μg/mL)                                 Antifungal                                                                            Candida albicans                                                      Agent   SLU-1                                                                              ATCC 10231                                                                           ATCC 18840                                                                           ATCC 26555                                                                           ATCC 44808                                                                           ATCC 90028                           __________________________________________________________________________    XMP.284 2.50 5.0    2.5    1.25   1.25   1.25                                   XMP.342 5.00 10.0 5.0 2.5 5.0 5.0                                             XMP.353 2.5                                                                   XMP.364                                                                       XMP.365 2.5 5.0 5.0 1.25 5.0 5.0                                              XMP.366 10.0 10.0 >10.0 10.0 >10.0 10.0                                       XMP.367 2.5 5.0 2.5 2.5 10.0 5.0                                              XMP.373 2.5 5.0 2.5 1.25 2.5 2.5                                              XMP.389 2.5 5.0 2.5 1.25 2.5 2.5                                              XMP.391 1.25 1.25 1.25 0.62 1.25 2.5                                          Amphotericin B 0.63 0.63 1.25 1.25 1.25 1.25                                  Fluconazole >10.0 >10.0 >10.0 >10.0 >10.0 >10.0                               Ketoconazole  >10.0 >10.0 >10.0 >10.0 >10.0                                 __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Antifungal Agent                                                                Minimum Fungicidal Concentration (μg/mL)                                         Candida                                                                            Candida                                                                             Cryptococcus                                                                         Fusarium                                                                           Trychophyton Aspergillus                         Anti- glabrata parapsilosis neoformans solani rubrum Aspergillus niger                                                   fungal ATCC ATCC ATCC ATCC                                                   ATCC ATCC ATCC                      Agent 2001 22019 13690 36031 28188 13073 16404                              __________________________________________________________________________    XMP.284 >10.0                                                                              >10.0 0.63   0.31 5.0    12.50 2.5                                 XMP.342 >10.0 >10.0 1.25 1.25 10.0 25.00 10.00                                XMP.353   0.63   12.50                                                        XMP.364                                                                       XMP.365 >10.0 10.0 1.25 0.16 10.0 25.00 5.00                                  XMP.366 >10.0 >10.0 1.25 10.0 >10.0 50.00 >10.00                              XMP.367 >10.0 10.0 1.25 0.31 >10.0 50.00 5.00                                 XMP.373 10.0 10.0 0.63 2.5 2.5 >50.00 2.50                                    XMP.389 5.0 5.0 0.63 1.25 5.0 25.00 1.25                                      XMP.391 5.0 2.5 0.31 0.31 2.5 12.50 1.25                                      Amphotericin B 0.32 5.0 1.25 0.62 0.32 12.50 5.00                             Fluconazole >10.0 >10.0 >10.0 >10.0 >10.0 >50.00 >10.00                       Ketoconazole >10.0 5.0  >10.0   >10.00                                      __________________________________________________________________________

In additional experiments, a fluorescence-activated cell sorter (FACS)based assay was developed to test the fungicidal activity of thepeptides. For these experiments, fungi were cultured and isolated byplating on Sabouraud's Dextrose (1% Neopeptone, 2% Dextrose; Difco)agar. Several colonies were picked from the agar plate and inoculatedinto 5 mL of Sabouraud's Dextrose media in a sterile 10 mL polypropylenetube. The fungal cultures were incubated for about 18 hours at 30° C. Atthe end of incubation, 4 mL of the fungal culture were inoculated into aflask of 100 mL of Sabouraud's Dextrose broth (SDB). The 100 mL culturewas inoculated for about 5 hours or until log growth. When the culturereached log growth, the 100 mL culture was decanted into two 50 mLconical popypropylene centrifuge tubes. The culture were centrifuged at3000 rpm for 5 minutes (Sorvall RT 6000B). After centrifugation, thesupernatant was decanted leaving the fungal pellets in the centrifugetubes. The pellets were resuspended in 15 mL of SDB. Both suspensionswere combined into one tube and mixed to generate a stock culture. Theconcentration of the fungal stock was determined by either diluting asample of the stock 1:10 with SDB and then determining the OD of thedilution by spectrophotometry at 570 nm (Shimadzu TV-160spectrophotometer) or by diluting the stock 1:10 with Trypan Blue andcounting the cells using a hemacytometer. After determining theconcentration of the stock, appropriate dilutions were made withSabouraud's Dextrose media to obtain 100 mL of 1×10⁶ cell/mL.

Peptide solutions were prepared in saline to concentrations ofapproximately 1 mg/mL. In a 96 well popypropylene plate (Costar 3790),the peptides were diluted 1:2 six times in a serial dilution with PBS.Then 1 mL of the 1×10⁶ cells/mL cell suspension was dispensed intoappropriate number of FACScan tubes (Falcon 2054), seven tubes perpeptide and three tubes for assay controls (positive, negative, andautofluorescence controls). Approximately 20 μl of the peptide solutionswere added to the 1 mL cell suspension to achieve a fmal peptideconcentration in the tube of 20, 10, 5, 2.5, 1.25, 0.625, and 0.313μg/mL peptide. The tubes were incubated at 30° C. for 1 hour except forthe positive control tube which was incubated for 40 minutes, thencentrifuged at 3000 rpm for 5 minutes. The supernatant was decanted andthe cell pellet was resuspended with I mL of 70% EtOI then incubated for10 minutes to achieve 100% kill. After the I hour incubation, all thetubes were centrifuged at 3000 rpm for 5 minutes. Supernatants weredecanted and the pellets resuspended with 1 mL of 80 μg/mL of propidiumiodide (Sigma, St. Louis, Mo.) in Dulbecco's PBS (DPBS, GIBCO, GrandIsland, N.Y.) except the autofluorescence control, which was resuspendedin DPBS alone. The tubes were mixed and incubated in the dark at roomtemperature for at least 20 minutes.

The FACScan flow cytometer (Becton Dickenson, Mountainview, Calif.) wasallowed to warm up for at least 5 minutes before assay analysis. Thesettings were adjusted appropriately to the following approximateparameters:

    ______________________________________                                                    Amplifier   Detector                                              ______________________________________                                        FSC           1.00-2.00     E00                                                 SSC 1.00-2.00 200-300                                                         FL1 Log 400-500                                                               FL2 Log 400-500                                                             ______________________________________                                    

Cells were analyzed (10,000 cells/tube) and their respectivefluorescence determined. In these experiments, the autofluorescentcontrol did not have significant fluorescence. The population of dead(i.e., propidium iodide stained) fungal cells was determined by afluorescence threshold between the negative control and positivecontrol. For all concentrations of peptides, the percentage of deadcells was plotted against peptide concentration and an IC₅₀ wasdetermined by curve fitting. The results for representative peptides areshown in Tables 5 through 8 below.

                  TABLE 5                                                         ______________________________________                                        Activity of peptides on C. albicans SLU#1                                             Peptide     IC.sub.50  (μg/mL)                                     ______________________________________                                        XMP.284         0.31                                                            XMP.353 0.53                                                                  XMP.268 0.55                                                                  XMP.342 0.60                                                                  XMP.391 0.64                                                                  XMP.391 0.73                                                                  XMP.391 0.73                                                                  XMP.366 0.89                                                                  XMP.389 0.95                                                                  XMP.373 1.13                                                                  XMP.342 1.88                                                                  XMP.342 2.03                                                                  XMP.465 2.11                                                                  XMP.367 2.37                                                                  XMP.406 4.29                                                                  XMP.378 13.09                                                                 XMP.407 27.03                                                                 Amphotericin B 79.36                                                        ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Activity of peptides on various strains of C. albicans                                                  IC.sub.50  (μg/mL)                                 Peptides SLU#1 10231 90028 26S55 14053                                      ______________________________________                                        XMP.284                                                                              0.31     1.86    1.08      0.59  0.50                                    XMP.342 1.88 8.07 3.44 3.19 2.74                                              XMP.365 2.11 3.75 0.27 0.15 0.13                                              XMP.366 0.89 4.53 2.29 0.69 1.35                                              XMP.367 2.37 ND 0.22 0.21 0.08                                                XMP.373 1.13 2.92 1.86 1.46 1.64                                              XMP.389 0.95 3.12 2.79 0.89 0.95                                              XMP.391 0.64 2.06 1.29 0.79 1.04                                            ______________________________________                                         ND = Not Determined                                                      

                  TABLE 7                                                         ______________________________________                                        Activity of Peptides on Various Candida Species                                             Candida      Candida                                                                              Candida                                        glabrata lusitaniae parasilosis                                               IC.sub.50 IC.sub.50 IC.sub.50                                                Peptide (μg/mL) (μg/mL) (μg/mL)                                    ______________________________________                                        XMP.284   6.27         1.20     1.82                                            XMP.342 11.00 3.24 NT                                                         XMP.365 15.26 1.25 7.72                                                       XMP.366 21.00 3.03 NT                                                         XMP.367 20.00 1.25 2.32                                                       XMP.373 4.96 1.11 3.74                                                        XMP.389 4.64 2.26 5.36                                                        XMP.391 2.85 1.69 0.85                                                      ______________________________________                                         NT = Not Tested                                                          

                  TABLE 8                                                         ______________________________________                                        Activity of Peptides on                                                         Crytococcus Neoformans 13690                                                         Peptide  IC.sub.50  (μg/mL)                                       ______________________________________                                               XMP.284                                                                              0.11                                                              XMP.342 0.95                                                                  XMP.353 0.37                                                                  XMP.365 0.03                                                                  XMP.366 0.47                                                                  XMP.367 0.05                                                                  XMP.373 0.87                                                                  XMP.389 0.25                                                                  XMP.391 0.34                                                                ______________________________________                                    

The effects of combinations of peptide and amphotericin B againstCandida strain SLU-1 were studied. For these experiments, Candidaalbicans SLU-1 was grown and assayed in a broth dilution assay asdescribed in Example 2, except that peptide alone, amphotericin B alone,or combinations of peptide and amphotericin B were incubated with thefungal cells for testing.

The results of such an assay using representative peptide XMEP.97, aloneor in combination with amphotericin B, are shown in FIG. 3. In FIG. 3,the fungicidal activity of combinations of XMP.97 and amphotericin B arerepresented for the XMP.97 concentrations shown and concentrations ofamphotericin B of 0.047 μg/ml (open squares); 0.074 μg/ml (closedtriangles); 0.188 μg/ml (open triangles; 0.375 μg/ml (closed circles);and 0.750 μg/ml (open circles). The activity of XMP.97 alone isrepresented by the closed squares. Both XMP.97 and amphotericin B areeach effective alone at certain concentrations as anti-fungal agents.The combination of peptide and amphotericin B does not result ininhibition (as it would if the two drugs were antagonistic), but ratherresults in decreasing the amount of both anti-fungal agents required formaximum killing. In particular, concurrent administration of this DomainIII derived peptide with an anti-fungal agent, such as amphotericin B,achieved an improved therapeutic effectiveness through reducing theconcentration of amphotericin B required to eradicate or inhibit fungalgrowth. Because the use of amphotericin B has been limited by itssystemic toxicity, lowering the concentration of such an anti-fungalagent required for therapeutic effectiveness can reduce toxicity, andthus may allow wider use of this agent.

The anti-fungal activity of Domain HI derived peptides may also beevaluated in vivo in animal models for a variety of fungal species,including Cryptospondium parvum, Cryptococcus neofonnans and Histoplasmacapsulstum. Animal models for C. parvum, sponsored by contract resourcesfrom the National Institute of Allergy and Infectious Diseases, includesevere combined immunodeficiency (SCID) mouse models and acolostrum-deprived SPF piglet model.

The anti-fungal activity of Domain III derived peptides may be evaluatedin vivo in additional animal models, including, for example, agranulocytopenic rabbit model of disseminated Candidiasis such asdescribed by Walsh et al., J. Infect. Dis., 161:755-760 (1990) andThaler et al., J. Infect. Dis., 158:80 (1988); a mouse model ofdisseminated Aspergillosis such as described by Arroyo et al.,Antimicrob. Agents & Chemo., pp. 21-25 (January, 1977); and aneutropenic rat model of disseminated Candidiasis such as described byLechner et al., Am. J. Physiol. (Lung Cell. Mol. Physiol.) 10:1-8 (1994)and references cited therein.

EXAMPLE 4 In Vivo Anti-Fungal Effect of Peptides in Mice with SystmeicCandida Infection

This example addresses the in Vivo anti-fungal effects of Domain IIIderived peptides in mitigating the total mortality or mortality rate ofmice systemically infected with Candida albicans. Peptides that had beenscreened for anti-fungal activity in the radial diffusion and brothassays described in Example 2 were prepared and purified as described inExample 1.

Groups of 15 male DBA/2J mice at age 6-8 weeks (Jackson Laboratory, BarHarbor, ME) were inoculated with 1.24×10⁵ C. albicans (SLU-1 strain asdescribed in Example 2) by intravenous injection into the tail vein.Cells were prepared for animal injection as follows. A single colony wasselected and used to inoculate a 5 mL tube of Sabouraud dextrose broth.Incubation was at 30° C. with shaking to allow aeration for a period of15-18 hours. Four mL of the overnight culture were added to 100 mL offresh Sabouraud dextrose broth (1:25 dilution) and incubated for 4hours. The 100 mL culture was pelleted at 1,500 X g for 5 minutes. Cellswere washed twice by adding 20 mL D-PBS, vortexing and re-centrifuging.Cells were collected in one tube and a sample is diluted 1:10 to bemeasured by OD₅₇₀ (1 OD unit=3×10⁷ CFU/mL). The cells were diluted tothe desired dose in D-PBS and kept at 4° C. until used. Doses wereconfirmed by performing serial ten-fold dilutions and plating 50 μl perdilution on Sabouraud dextrose agar. Colonies were counted the followingday after overnight incubation at 37° C. A 500 mL culture yieldedapproximately 1×10⁹ CFU/mL.

A Candida inoculation of approximately 1×10⁵ cells resulted in an LD80over 28 days in this model. Immediately after fungal challenge, the micewere intravenously injected via the tail vein with a 0.1 mL volume of 10mg/kg P.36, 5 mg/kg XMP.97, 10 mg/kg XMP.102, 1 mg/kg amphotericin B(Sigma, St. Louis, Mo.), or phosphate buffered saline (PBS) as acontrol. Treatment with the same amounts of peptides, amphotericin B orPBS was repeated at Day 2 and Day 4 (except that the second dose ofXMT.36 was given at a dose of 5 mg/kg). Mice were monitored twice dailyfor mortality until termination of the study at Day 28. The mortalitydata, displayed in FIG. 4, show that 100% of the mice treated withamphotericin B survived, 53% of mice treated with XMP.97 survived(p<0.05 compared to control), 33% of mice treated with XMP.36 survived,27% of mice treated with XMP.102 survived, and 20% of mice treated withPBS survived until Day 28. In FIG. 4, the symbol "X" represents survivalafter treatment with amphotericin B; open squares, treatment withXMP.97; open circles, treatment with XMT.36; open diamonds, treatmentwith XMP. 102; and open triangles, treatment with buffer. Statisticalsignificance was evaluated using the Lifetest Survival Curve analysis.[Lawless, Statistical Models and Methods for Lifetime Data, John Wiley &Sons, New York (1982).] The duration and almost linear decline insurvival is analogous to human opportunistic candidiasis.

In additional 3-dose studies, groups of 15 mice were injected with afungal challenge of 0.5×10⁵ Candida cells, prepared for injection asdescribed above, followed by treatment at Day 0, Day 2 and Day 5 with a0.1 mL volume of 10 mg/kg XMP.127, 5 mg/kg XP.13, 5 mg/kg XMP.37, 1mg/kg amphotericin B, or PBS as a control. The mortality data aredisplayed in FIG. 5; 100% of the mice treated with amphotericin Bsurvived, 67% of mice treated with XMP. 127 survived (p <0.05 comparedto control), 33% of mice treated with XMP.37 survived, 20% of micetreated with XMP.13 survived, and 33% of mice treated with PBS surviveduntil Day 28. In FIG. 5, the symbol "X" represents survival aftertreatment with amphotericin B; open circles, treatment with XMP. 127;filled triangles, treatment with buffer; open squares, treatment withXMP.37; open triangles, treatment with At XMP.13.

In these 3-dose studies, amphotericin B was completely protective, asexpected. The effect of XMP.102, a control peptide without anti-fungalactivity as determined by a radial diffusion assay as described inExample 2, was no different from PBS. The data demonstrate thatadministration of peptides XMP.97 and MP. 127 to mice challengedsystemically with C albicans unexpectedly provided a significantreduction in mortality compared with buffer-treated controls.

Further studies to determine the effectiveness of anti-fungal peptideswere performed at an increased dosing regimen (6 doses rather than 3doses as described above). Groups of 9 week-old male DBA/2J mice wereinoculated with concentrations of 2.7×10⁵ Candida cells (prepared asdescribed above) by intravenous injection in the tail vein. Immediatelyafter fungal challenge, the mice were treated with a 0.I mL volume of 10mg/kg XMP.284, 1 mg/kg amphotericin B or PBS as a control at Day 0 , Day2, Day 4, Day 7, Day 9 and Day 11. All amphotericin B-treated animalswere protected. The results for XMP.284 (closed circles) and PBS control(open circles) are displayed in FIG. 6. The mortality data showed thatonly one of the PBS-treated animals survived injection with 2.7×10⁵Canada at Day 6 through Day 24 (6% survival), however, XMP.284 protected13 animals (87% survival) at Day 6 and 3 animals (33% survival) at Day24.

Additional 6-dose experiments were conducted as described above, usinginocula of 0.5-3.0×10⁵ Candida cells and using 0.01, 0.05, 0.1, 0.5, 1.0or 5.0 mg/kg doses of peptide. The results are summarized in Table 9below.

                  TABLE 9                                                         ______________________________________                                        Peptide   Dose (mg/kg)  P-value.sup.a                                         ______________________________________                                        XMP.268   5, 0.5        b, b                                                    XMP.327 5, 0.5 b, b                                                           XMP.332 5, 0.5 b, b                                                           XMP.333 5, 0.5 b, b                                                           XMP.334 5, 0.5 0.002, 0.001                                                   XMP.335 5, 0.5 b, b                                                           XMP.338 5, 0.5 b, b                                                           XMP.342 5, 0.5 0.02, b                                                        XMP.344 5, 0.5 0.0005, 0.0004                                                 XMP.345 5, 0.5 0.0001, 0.0001                                                 XMP.347 5, 0.5 0.0001, 0.0001                                                 XMP.348 0.5 0.0001                                                            XMP.349 5, 0.5 0.0003, b                                                      XMP.352 5, 0.5 b, b                                                           XMP.353 5, 0.5 0.0001, 0.0002                                                 XMP.355 5, 0.5 b, b                                                           XMP.356 1, 0.5 b, b                                                           XMP.357 5, 0.5 b, 0.01                                                        XMP.358 5, 0.5 b, b                                                           XMP.363 5, 0.5 0.0001, 0.0001                                                 XMP.364 5, 0.5 0.0002, b                                                      XMP.365 0.5, 0.1, 0.05, 0.01 0.0001, 0.01, 0.0008, 0.0002                     XMP.366 0.5, 0.1, 0.05, 0.01 0.0001, b, b, b                                  XMP.367 5, 0.5 0.001, b                                                       XMP.368 5, 0.5 b, b                                                           XMP.369 5, 0.5 b, b                                                           XMP.370 5, 0.5 b, b                                                           XMP.371 5, 0.5 b, b                                                           XMP.372 5, 0.5 b, b                                                           XMP.373 5, 0.5 b, b                                                           XMP.374 0.5 b                                                                 XMP.375 5, 0.5 b, b                                                           XMP.376 5, 0.5 b, b                                                           XMP.377 5, 0.5 b, b                                                           XMP.381 5, 0.5 b, b                                                           XMP.385 5, 0.5 b, b                                                           XMP.386 5, 0.5 b, b                                                           XMP.387 5, 0.5 b, b                                                           XMP.388 5, 0.5 0.003, b                                                       XMP.389 5, 0.5 0.0003, b                                                      XMP.391 5, 0.5 0.05, b                                                        XMP.410 5, 0.5 b, b                                                           XMP.414 1, 0.5 b, b                                                           XMP.416 0.5 0.02                                                            ______________________________________                                         .sup.a Pvalues vs. saline are derived from KaplanMeier survival analysis      .sup.b not statistically better than saline (P > 0.05)                   

An in Wvo fungicidal assay was developed to study the comparativeefficacy of peptides and Amphotericin B (AmpB) to reduce fungal load inthe kidneys of mice systemically infected with Candida albicans.Experiments were designed to determine the extent of fungal clearancefrom the kidneys following peptide or AmpB treatment as follows.

Inoculation of male DBA/2 mice (Charles River Labs) with 6×10⁴ C.albicans and administration of saline, AmpB or peptide was performed onDay 0 via intravenous injection into the tail vein. All groups (n=6)received equal C. albicans challenge (standard inoculum of 1.0-1.5×10⁵reduced by half to avoid mortality) and equal total volume of sterilesaline or antifungal agent per injection. Treatment was initiatedimmediately after inoculation. All mice were dosed q.d. or q.o.d. withsaline, peptide or Amp B. At study termination on Day 4, all animalswere sacrified by CO₂ asphyxiation and their kidneys excised for Codare-isolation.

Specifically, immediately following animal sacrifice, both kidneys wereexcised, and adrenal glands and adhering tissue removed. Pairs ofkidneys were placed immediately into pre-weighed 15 mL conical tubescontaining 5 miL sterile saline plus a 1:100 dilution of a 10 mg/mLstock solution of peniclllin/streptomycin. Tubes were weighed again, andthe difference recorded as "kidney gram fresh weight." Tubes were storedon ice until organ maceration.

For Candda re-isolation and CFU determination, a glass-on-glass tissuehomogenizer (Tenbroeck Tissue Grinder, 15 mL, Wheaton) was washed withsoap and water, rinsed, and sterilized for 2 minutes with ice-cold 70%ethanol. Following decanting of the ethanol, homogenizers were rinsedwith sterile PBS, which was also decanted. Then 5 mL ofsaline/antibiotics and kidneys were added to the prepared homogenizerand ground until kidney capsules were free of adhering tissue. 2 mL ofthis homogenate was transferred sterilely to a clean tube on ice. 100 μLof homogenate (serially diluted in sterile PBS) were plated ontoSabouraud Dextrose Agar plates and incubated at 37° C. overnight.Colonies were enumerated, CFU and CFU/GFW calculated, and resultsanalyzed by ANOVA and Fisher's PLSD. The results of assays withrepresentative peptides are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                        Peptide  Dose (mg/kg)  Dose Regimen                                                                              P-value.sup.a                              ______________________________________                                        XMP.366  0.5           single dose 0.0005                                        0.1 q.d b                                                                     0.05 q.d., b.i.d. b, b                                                        0.01 q.d., b.i.d. 0.008, b                                                   XMP.342 5 q.d., q.o.d. b, b                                                    1 q.d. b                                                                     XMP.391 5 q.d., q.o.d. 0.002, b                                                1 q.d. b                                                                     XMP.373 5 q.d., q.o.d. b, b                                                    1 q.d. b                                                                     XMP.353 5 q.d., q.o.d. b, b                                                    1 q.d. b                                                                   ______________________________________                                         .sup.a Pvalues vs. saline are derived fmm KaplanMeier survival analysis       .sup.b not statistically better than saline (P > 0.05)                   

Studies were also performed to determine the effectiveness ofrepresentative anti-fungal peptides in cyclosporin A-immunosuppressedmice systemically infected with Candida albicans SLU-1. Groups (15animals/group) of 9 week-old male DBA/2J mice were immunosuppressed bypretreatment with 10 mg/kg (Day-1) of cyclosporin A administered byintraperitoneal injection. One day later (Day 0), the mice wereinoculated with 2×10⁵ Candida cells by intravenous injection in the tailvein. Immediately after fungal challenge, the mice were treated with a0.1 mL volume of 10 mg/kg XNP.284, 10 mg/kg XMP.127, or PBS as acontrol. Cyclosporin A injections were repeated at Day 1. Day 3, Day 7,and Day 9. XMP.284, XMT. 127 or PBS injections were repeated at Day 2,Day 4, Day 6, Day 8 and Day 10. All amphotericin B-treated animals wereprotected. The results displayed in FIG. 7 of the mortality data aftertreatment with XMP. 127 (open squares), XMP.284 (closed triangles). andPBS control (open circles) show that the immunosuppressed mice are moresusceptible to Candida infection as expected. However, XMP.284 and to alesser extent XMP. 127, provided protection against the infection asmeasured by increased survival compared with PBS controls.

Further in Vivo experiments with or without cyclosporin Aimmunosuppression are performed to confirm the in vitro anti-fungalactivity of peptides as described in Example 3 on strains of Candidaconsidered resistant to other anti-fungal agents: polyene-resistant C.albicans (ATCC Accession No. 38247), 5-fluorocytosine-resistant C.albicans (ATCC No. 44373), azole-resistant C. albicans (ATCC No. 62342),and ketoconazole-resistant C. albicans (ATCC No. 64124).

EXAMPLE 5 Serum Stability Assays

This example addresses the serum stability of Domain III derivedpeptides and the effect of serum degradation using HPLC and bioassay.

For these serum stability experiments, peptides were prepared by solidphase peptide sythesis and purified to 94% or greater purity asdescribed in Example 1. Blood was collected from metaphane anesthesizedrats by aortic bleed into Vacutainer™ tubes and allowed to clot at roomtemperature for approximately 30 minutes, then centrifuged at 3000 rpm(about 1000 X g) for 10 minutes at room temperature and the serumaspirated. In addition, frozen human serum (North American Biologics,Inc., Miami, Fla., cat. no. 2140, lot no. 94115) was thawed at roomtemperature and filtered through a 0.45 im membrane before use.

A 1 mg/mL solution of an exemplary XMP peptide to be tested was added toan equal volume of either rat or human serum described above andmaintained at 37° C. At 0, 1, 2, and 4 hours, 100 μL were removed andprocessed by solid phase extraction for HPLC analysis as follows. Serumsamples were prepared for HPLC using C-18 Sep-Pak cartridges (1 mLcartridge with 100 mg of sorbent, Waters Corp., Milford, Mass.). Onehundred μL of serum sample were added to an equal volume of 1% TFA andmixed for 30 seconds on a Vortex mixer. The sample was then applied to aC-18 SepPak cartridge that had been conditioned by washing with 1 mL ofmethanol followed by 1 mL Milli-Q water. Weakly retained components wereeluted by washing with 1 mL of 0.1% TFA. The bound peptide was elutedwith two volumes of 250 lL 80% acetonitrile/0.065% TFA.

The material eluted from the Sep-Pak cartridge was analyzed on a MichromUltrafast Microprotein Analyzer equipped with a 150 mm×1 mm, 5 μparticle, 300 Å pore C-8 Zorbax column. The column oven was set to 40°C., the flow rate was 100 μL/minute, and injection volumes weretypically 5-10 μL. HPLC was performed using 5% acetonitrile/0.1% TFA inwater as mobile phase A, and 80% acetonitrile/0.065% TFA as mobile phaseB. The eluate was monitored spectrophotometrically at 214 nm. Peptidestandards were dissolved in mobile phase A at 0.1 mg/mL. The gradientwas 25-35% B/10 minutes followed by a 5 minute wash step of 100% B andreequilibration at 25% B for 10 minutes.

The peptides identified and purified after serum incubation as describedabove were subjected to N-terminal peptide sequencing performed on anApplied Biosystems Model 477A/120A sequencer and to electrosprayionization mass spectrometry (ESI/MS) performed using a VG Biotech Bio-QMass Spectrometer. In addition, the peptides identified and purifiedafter serum incubation as described above were also tested for theiranti-fungal activity in a radial diffusion bioassay with Candidaalbicans SLU-1 strain as described in Example 2.

For these experiments, representative Domain III derived peptidesXMP.97, XMP.327, XMP.332 and XMP.333 were used. The serum stability ofeach differed substantially. For example, XMP.97 was degraded in serumwith a half-life of 59 minutes under the described assay conditions. Twometabolites of XMIP.97 were detected and were determined to be cleavageproducts where the cleavage at the amino terminus yielded peptidesshortened by either one or two amino acids. The degradation products andkinetics were similar for commercially obtained human serum or freshlyprepared rat serum. Other metabolic products of XMP.97 were presumablypresent but in concentrations below detection limits.

The chemical changes observed after serum incubation of a peptide weregenerally accompanied by a loss in activity as determined in the radialdiffusion assay with Candida. For example, XMP.327 was degraded with aserum half-life of 40 minutes under the described HPLC assay conditions.The serum half-life of XMP.327 as determined by anti-fungal activity inthe radial diffusion assay was 43 minutes. In other cases, there may bea difference between the rate of disappearance of anti-fungal activityand the rate of peptide disappearance, indicating that certainmetabolites may have activity.

The enzymes responsible for peptide degradation were not specificallyidentified in these experiments. However, aminopeptidases present inserum are capable of removing one or more residues from the N-terminusof peptides. [See, e.g., Hooper, N. M., Ectopeptidases, in BiologicalBarriers to Protein Delivery, pp.23-50, eds., Audus and Raub, PlenumPress, New York, 1993]. Aminopeptidase N (EC 3.4.11.2), for example, hasa broad substrate specificity, releasing the N-terminal amino acid fromunblocked peptides. Based on sites of potential hydrolysis, peptides canbe designed to minimize certain degradation pathways. Serum degradationat specific amino acids within a peptide may be avoided by incorporationof D-amino acids or other atypical amino acids, and/or by cyclization toprevent protease recognition.

In additional studies, peptides were designed to have increased serumstability. For example, peptides were synthesized using one or moreD-amino acids. Also, peptides were synthesized and then their N-terminuswas acetylated as described in Example 1. For example, XMP.333 wassynthesized having the same amino acid sequence as XMP.327, except thatthe amino-terminal lysine residue used for synthesis was a D-amino acid.When XMP.333 was tested, its serum half-life as determined in the radialdiffusion assay was 130 minutes (as compared with 43 minutes forXMP.327). These results indicate that a single D-amino acid at theN-terminus prevents some degradation and increases the half-life of thepeptide.

Peptide constructs can be prepared with increased half-life, but may notmaintain the same in vitro activity. For example, XMP.327 had a serumhalf-life of 43 minutes and activity in radial diffusion of 353 pmol(see Table 1). Peptide XMP.331 having the same amino acid sequence ofXMT.327 but having an acetylated N-terminus, had an increased serumhalf-life of 280 minutes as detected by HPLC analysis, but a decreasedactivity of >3,493 pmol (see Table 1) as compared with thenon-acetylated XMP.327. However, even with decreased in vitro activity,such a peptide may have increased efficacy in vivo due to its increasedstability.

Other peptide constructs can be prepared with not only significantlyincreased stability but also with maintained anti-fungal activity in theradial diffusion assay. For example, XMP.332 was synthesized using allD-amino acids and is the inverse sequence of XMP.327. Such a "retro-D"peptide should be resistant to serum enzymes that recognize andhydrolyze the peptide bond between L-amino acids. In fact, XMP.332 didnot show any decrease in activity or decrease in peptide concentrationover a 6 hour period of serum incubation. Such a peptide construct,which can maintain the in vitro equivalent molar activity to its L-aminoacid peptide counterpart and shows increased serum half-life, may haveincreased efficacy in vivo. The half-life of the activity in serum asmeasured by radial diffusion assays and the half-life of peptide inserum as detected by EPLC analysis are shown in Table 11 forrepresentative peptides.

                  TABLE 11                                                        ______________________________________                                                                 Activity in                                                                            HPLC Peptide                                  Peptide Peptide Amino Serum in Serum                                          (SEQ. ID NO.) Acid Segment t1/2 (hr.) t1/2 (hr.)                            ______________________________________                                        XMP.13 (4)                                                                             141-169         indefinite                                                                             2.5                                           XMP.97 (31) 148-161, K @ 152 (G) 22.7 1.0                                     XMP.132 (52) 148-161, PYR @ 153 9.7 NT                                         (W)                                                                          XMP.133 (53) 148-161, p-Amino-F @ 14.0 NT                                      153 (W)                                                                      XMP.139 (58) 148-161, Y @ 153 (W) 10.6 NT                                     XMP.268 (108) 148-161, V @ 153 (W), A 15.3 NT                                  @ 154 (L)                                                                    XMP.284 (117) 149-161, K @ 152 (G) 14.6 4.2                                   XMP.327 (160) K-K-153-157-K-K 2.7 1.1                                         XMP.331 (162) $K-K-153-157-K - inactive 4.0                                    K                                                                            XMP.332 (163) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D -                                          indefinite indefinite                          W.sub.D -K.sub.D -K.sub.D                                                    XMP.333 (164) K.sub.D -K-153-157-K-K 2.2 2.3                                  XMP.334 (165) P.sub.D -K-153-157-K-K 4.7 3.2                                  XMP.335 (166) P-K-153-157-K-K 1.3 2.9                                         XMP.337 (168) H-H-153-157-H-H inactive NT                                     XMP.338 (169) ORN-ORN-153-157- 4.7 NT                                          ORN-ORN                                                                      XMP.342 (173) K.sub.D -K.sub.D -153-157-K.sub.D - indefinite 5.2                                                K.sub.D                                     XMP.344 (175) K-K-153-157-K-K, 3.3 0.6                                         A @ 154 (L)                                                                  XMP.345 (176) K-K-153-157-K-K, 2.7 1.4                                         A @ 157 (L)                                                                  XMP.347 (178) K-K-153-157-K- 5.2 2.5                                           K, β(2-naphthyl) A.sub.D @ 153                                           (W), L @ 156 (Q)                                                             XMP.348 (179) K-K-K-153-157-K- 5.5 NT                                          K                                                                            XMP.349 (180) K-K-153-157-K-K- 3.3 1.4                                         K                                                                            XMP.351 (182) K-K-153-158-K-K 0.4 NT                                          XMP.352 (183) K-K-153-161 1.2 0.7                                             XMP.353 (184) P-153-161* 0.9 NT                                               XMP.355 (186) P-153-161 5.7 3.2                                               XMP.356 (187) $ P-153-161 0.9 NT                                              XMP.357 (188) K-153-160-P 0.8                                                 XMP.358 (189) K-K-153-160-P 1.6                                               XMP.363 (194) K.sub.D -W.sub.D -154-159-K.sub.D - indefinite 11.8                                               K.sub.D                                     XMP.364 (195) $ K.sub.D -W.sub.D -154-159- indefinite 25.0                     K.sub.D                                                                      XMP.365 (196) K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D - 15.1 26.3                                           L.sub.D -F.sub.D -H.sub.D -K.sub.D                                          -K.sub.D                                      XMP.366 (197) $ K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D - 11.7 14.0        L.sub.D -F.sub.D -H.sub.D -K.sub.D -K.sub.D                                  XMP.367 (198) K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D - indefinite                                        52.4                                           Q.sub.D -I.sub.D -L.sub.D -W.sub.D -K.sub.D                                  XMP.368 (199) $ K.sub.D -K.sub.D -H.sub.D -P.sub.D -L.sub.D - 25.2 34.1        Q.sub.D -I.sub.D -L.sub.D -W.sub.D -K.sub.D                                  XMP.369 (200) 152-161, K @ 152 (G), 1.4 0.6                                    ORN @ 156 (Q)                                                                XMP.370 (201) $ 152-161, K @ 152 (G), 4.7 2.9                                  ORN @ 156 (Q)                                                                XMP.371 (202) 152-161, K @ 152 (G), 0.9                                        DAB @ 156 (Q)                                                                XMP.372 (203) $ 152-161, K @ 152 (G), 1.4 6.6                                  DAB @ 156 (Q)                                                                XMP.373 (204) $ 152-161, K @ 152 (G) 1.8 2.6                                  XMP.374 (205) K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D - indefinite                                        indefinite                                     W.sub.D -K.sub.D -K.sub.D                                                    XMP.375 (206) K.sub.D -K.sub.D -W.sub.D -A.sub.D -I.sub.D - indefinite                                        indefinite                                     Q.sub.D -L.sub.D -K.sub.D -K.sub.D                                           XMP.376 (207) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D -A.sub.D -                                          indefinite indefinite                          W.sub.D -K.sub.D -K.sub.D                                                    XMP.377 (208) K-K-K-W-A-I-Q- 1.8 NT                                            L-K-K                                                                        XMP.379 (210) K-K-P-W-A-I-Q- 0.3 0.8                                           L-K-K                                                                        XMP.381 (212) K-K-L-Q-L-L-L- 0.8 NT                                            K-K                                                                          XMP.385 (216) K-K-L-L-L-L-L- 2.7 NT                                            K-K                                                                          XMP.386 (217) 152-161, K @ 152 (G), A 0.9 NT                                   @ 154 (L)                                                                    XMP.387 (218) 152-161, P @ 152 (G), A 2.3 2.8                                  @ 154 (L)                                                                    XMP.388 (219) 152-161 1.4 0.4                                                 XMP.389 (220) 151-161, K @ 151 (V) 1.6 1.3                                    XMP.391 (222) 150-161 4.7 1.0                                                 XMP.410 (241) CH.sub.3 --(CH.sub.2).sub.6 --CO-- 2.9 NT                        XMP.344                                                                      XMP.411 (242) CH.sub.3 --(CH.sub.2).sub.10 --CO-- 4.2 9.7                      XMP.344                                                                    ______________________________________                                    

EXAMPLE 6 Structure/Function Studies

This example addresses the design and assay of anti-fungal peptides forstructural motif and minimum functional sequence analysis.

As shown in Examples 2, 3, and 4 above, XMP.97 was determined to havesignificant in vitro activity against C. albicans and significant invivo activity in a mouse systemic candidiasis model. The sequence wasderived from XMP. 13 with a lysine substitution for glycine at position152 in the BPI sequence. As shown in Example 5, sequential N-terminalamino acid removal was observed when the peptides, including XMP.97,were incubated with serum. The 13 amino acid peptide XMP.284(SKVKWLIQLFHKK-amide; SEQ. ID. NO: 1 17) was synthesized, purified (97%)and tested for anti-fungal activity. The in vitro activity wassurprisingly not appreciably diminished (see Table 1). A deletion seriesof 35 peptides was generated from this starting sequence. All possibleN- and C- terminal deletion 12-mers through 6-mers XMP.285-XMP.319) weresynthesized as shown in Table 12 below.

Crude peptides were assayed for an initial purity as described inExample 1 and for in vitro activity with the radial diffusion fungicidalassay as described in Example 2. The nmol value shown in Table 12represents a calculated value (log titration curve) for the number ofnanomoles required to achieve a net 30 mm² zone in the assay. Inpurifying XMP.97 and XMP.284, a significant change was observed in thepmol value upon purification. The magnitude of change was larger thanobserved with other crude peptides and was likely due to removal ofinactive peptide impurities. Thus, final comparisons were made usingpeptides purified as described in Example 1, and preferably asssayed onthe same day.

The most active crude peptides were purified by IPLC and re-assayed. Theresults are shown in Table 12. From this analysis, as demonstrated byTable 12, XMP.293 was the smallest peptide with an increase in molaractivity relative to peptide XMP.97. XMP.297 was also equivalent toXMP.284 in activity. Interestingly, XMP.298 was within two-fold ofXMP.297. Activity was demonstrable even with 6 amino acid peptides, suchas XMP.315, however, this level of activity was decreased by about 3orders of magnitude compared with the activity of the starting sequence.

These data demonstrate that one group of Domain III derived peptides ofthe invention are described and defmed by a structural motif consistingof a core of 4 to 6, preferably 5 to 6, amino acids where the corecontains one neutral hydrophilic residue in the middle of hydrophobicamino acids, and where the core is bounded or flanked at the N- and/orC-terminus by cationic amino acids. Preferred core sequences include:L1QL, IQLF, WLIQP, LIQLF and WLIQLF. Preferred cationic amino acidsinclude: K (most preferred), R, H, ornithine (ORN) and diaminobutyricacid (DAB). Peptides with such a motif possess optimal activity.Activity was observed, but was somewhat diminished, when the peptidecontained all of the cationic residues on the C-terminus (e.g., XMP.298)or on the N-terminus (e.g., XMP.300) of the core. Peptides XMP.320 -XMP.368 were designed and prepared consistent with this motif, andprovide additional support for the structural motif and minimumfunctional characterization sequence of anti-fungal peptides accordingto the invention.

                                      TABLE 12                                    __________________________________________________________________________                                                            Cru-                         de                                                                          AMINO ACID SEQUENCE Plate Pur- Plate                                     Length                                                                            Pep-              152                           Assay                                                                             ity                                                                              Assay                in a.a.sup.a tide MW 148 149 150 151 .sup.mb 153 154 155 156 157 158                                                                   159 160 161                                                                   (nmol).sup.b                                                                  (%) (nmol).sup.                                                               c                  __________________________________________________________________________    14  97 1782                                                                             K  S  K  V  K  W  L  I  Q  L  F  H  K  K  0.701                                                                             68 0.304                13 284 1654 • S K V K W L I Q L F H K K 1.460 60 0.373                  12 285 1526 • S K V K W L I Q L F H K • >3.024 75                  286 1527 • • K V K W L I Q L F H K K 1.216 61 0.253                                                                        11 287 1398                                                                  • S K V                                                                 K W L I Q L F                                                                 H •                                                                     • >3.509                                                                58                    288 1439 • • K V K W L I Q L F H K • 3.639 78 0.279                                                                   289 1439                                                                    •                                                                       •                                                                       • V K W                                                                 L I Q L F H K                                                                 K 1.542 78                                                                    0.68                 10 290 1261 • S K V K W L I Q L F • • • >2.233                                                                 79                    291 1311 • • K V K W L I Q L F H • • >5.039 55        292 1311 • • • V K W L I Q L F H K • >4.063 78        293 1340 • • • • K W L I Q L F H K K 1.156 78                                                                 0.215                9 294 113 • s K V K W L I Q L • • • •                                                                    >4.634 63                                                                       295 1174                                                                    •                                                                       • K V K                                                                 W L I Q L F                                                                   •                                                                       •                                                                       • >1.977                                                                82 >2.612                                                                       296 1183                                                                    •                                                                       •                                                                       • V K W                                                                 L I Q L F H                                                                   •                                                                       • >5.573                                                                .64                   297 1212 • • • • K W L I Q L F H K •                                                                    1.817 81 0.564        298 1212 • • • • • W L I Q L F H K K                                                                    2.628 84 1.106       8 299 1000 • S K V K W L I Q • • • •                                                                     • >8.768                                                                68                    300 1026 • • K V K W L I Q L • • •                                                                      • 1.957                                                                 75 0.993                                                                        301 1045                                                                    •                                                                       •                                                                       • V K W                                                                 L I Q L F                                                                     •                                                                       •                                                                       • -- 41                                                                   302 1083                                                                    •                                                                       •                                                                       •                                                                       • K W L                                                                 I Q L F H                                                                     •                                                                       • >5.497                                                                75 2.07                                                                         303 1083                                                                    •                                                                       •                                                                       •                                                                       •                                                                       • W L I                                                                 Q L F H K                                                                     • >4.694                                                                78 1.306                                                                        304 1025                                                                    •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       • L I Q                                                                 L F H K K                                                                     >8.290 84                                                                      7 305 872.1                                                                  • S K V                                                                 K W L I                                                                       •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       >10.228 73                                                                      306 913.2                                                                   •                                                                       • K V K                                                                 W L I Q                                                                       •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       >10.485 62                                                                      307 898                                                                     •                                                                       •                                                                       • V K W                                                                 L I Q L                                                                       •                                                                       •                                                                       •                                                                       • >8.345                                                                67                    308 946 • • • • K W L I Q L F • •                                                                 • -- 72                                                                   309 955                                                                     •                                                                       •                                                                       •                                                                       •  W L I                                                                Q L F H                                                                       •                                                                       • -- 76                                                                   310 897                                                                     •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       • L I Q                                                                 L F H K                                                                       • >9.475                                                                56                    311 912 • • • • • • • I Q L                                                                 F H K K -- 77                                                                  6 312 759                                                                    • S K V                                                                 K W L •                                                                 •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       • >11.20                                                                76                    313 785 • • K V K W L I • • • •                                                                   •                                                                       • >11.05                                                                59                    314 785 • • • V K W L I Q • • •                                                                   •                                                                       • 13.497                                                                73                    315 799 • • • • K W L I Q L • •                                                                   •                                                                       • >5.069                                                                84 >12.853                                                                      316 818                                                                     •                                                                       •                                                                       •                                                                       •                                                                       • W L I                                                                 Q L F •                                                                 •                                                                       • 11.1                                                                  85 inactive                                                                        to 11.5                                                                    317 169                                                                     •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       • L I Q                                                                 L F H •                                                                 • --                                                                      318 784                                                                     •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       •                                                                       • I Q L                                                                 F H K •                                                                 --                    319 799 • • • • • • •                                                                       • Q L F                                                                 H K K --           __________________________________________________________________________     .sup.a a.a. = amino acids                                                     .sup.b crude peptide activity                                                 .sup.c pure peptide acitivity                                            

EXAMPLE 7 LPS Neutralization Activity of Anti-Fungal Peptides

This example addresses the in vitro and in vivo LPS neutralizingactivity of Domain III derived peptides.

An in vitro LPS neutralization screening assay for evaluation of DomainIII derived peptides was developed (as described in co-owned andco-pending U.S. patent application Ser. No. 08/306,473) which providesboth a measure of efficacy of each peptide (EC₅₀) and of thetoxicity/growth inhibition of each peptide (IC₅₀. This sensitive assayfor inhibition of cellular proliferation in mouse cells treated with LPScan also be utilized for quantitation of LPS levels in human plasma upondevelopment of a standard curve.

In this assay, mouse RAW 264.7 cells (ATCC Accession No. TIB71),maintained in RPMI 1640 medium (GBCO), supplemented with 10 mM YESbuffer (pH 7.4), 2 mM L-glutamine, penicillin (100 U/mL), streptomycin(100 ag/mL), 0.075% sodium bicarbonate, 0. 15M 2-mercaptoethanol and 10%fetal bovine serum (Hyclone, Inc., Logan, Utah), were first induced byincubation in the presence of 50 U/mL recombinant mouse y-interferon(Genzyme, Cambridge, Mass.) for 24 h prior to assay. Induced cells werethen mechanically collected and centrifuged at 500 x g at 4° C. and thenresuspended in 50 mL RPMI 1640 medium (without supplements),re-centrifuged and again resuspended in RPMI 1640 medium (withoutsupplements). The cells were counted and their concentration adjusted to2×10⁵ cells/mL and 100 μL aliquots were added to each well of a 96-wellmicrotitre plate. The cells were then incubated for about 15 hours withE. coil 0113 LPS (Control Standard, Assoc. of Cape Cod, Woods Hole,Mass.), which was added in 100 μL/well aliquots at a concentration of 1ng/mL in serum-free RPMI 1640 medium (this concentration being theresult of titration experiments in which LPS concentration was variedbetween 50 pg/mL and 100 ng/mL). This incubation was performed in theabsence or presence of peptides in varying concentrations between 25ng/mL and 50 μg/mL. Recombinant human rBPI₂, also designated rBPI₂₁Δcys, which is rBPI 1-193, with alanine substituted at position 132 forcysteine [see co-owned U.S. Pat. No. 5,420,019] was used as a positivecontrol at a concentration of 1 μg/mL. Cell proliferation wasquantitatively measured by the addition of 1 μCi/well [MH]-thymidine 5hours after the time of initiation of the assay. After the 15-hourincubation, labeled cells were harvested onto glass fiber filters with acell harvester (Inotech Biosystems, INB-384, Sample Processing andFilter Counting System, Lansing, Mich.).

The LPS-mediated inhibition of RAW 264.7 cell proliferation is dependenton the presence of LBP, as added to the reaction mixture either as acomponent of serum or as recombinant LBP (at a concentration of 1μg/mL). Different patterns of peptide behavior are observed in theassay. The Domain III derived anti-fungal peptides with LPS-neutralizingactivity according to the present invention generally did not exhibit anIC₅₀ at the concentrations tested, unlike other XMP peptides includingLPS-neutralizing peptides that are not anti-fungal, as described incrowned and co-pending U.S. applications Ser. Nos. 08/209,762 and08/306,473. For example, XMP.5 displayed an EC, (i.e., the peptideconcentration at which the growth inhibitory effect of LPS was reversedby 50%) of 5.3±0.6 μg/mL; however, an IC₅₀ (i.e., the peptideconcentration at which RAW cell growth was inhibited by 50% from thevalue without added LPS or peptide) was not observed at theconcentrations tested. The results of a representative assay ofexemplary Domain Im derived anti-fungal peptides are shown in FIG. 8.The LPS-neutiuiizing activities of the purified anti-fungal peptidesXMP.327 (open squares), XMP.332 (closed squares), XMP.333 (opentriangles) and XMP.337 (closed triangles) are shown in FIG. 8. Alsoshown as a positive control is the activity of rBPI₂₁. Results fromrepresentative peptides tested with this assay are shown in Table 13.

                                      TABLE 13                                    __________________________________________________________________________                              In Vitro LPS                                          Peptide Peptide Amino HPLC % Neutralization                                 (SEQ ID NO:)                                                                          Acid Segment Purity                                                                             EC.sub.50.sup.a μg/ml                                                             IC.sub.50.sup.b μg/ml                     __________________________________________________________________________    XMP.97P (31)                                                                          148-161, K @ 152 (G)                                                                       98   3.69 + 0.46                                                                          >25                                            XMP.127 (47) 148-161, F @ 153 (W) 63 10.77 + 1.34 NA                          XMP.284P (117) 149-161, K @ 152 (G) 96 4.72 + 0.08/ NA/                          3.57 + 0.09 >50                                                            XMP.286P (119) 150-161, K @ 152 (G) 80 4.68 + 0.26 NA                         XMP.288P (121) 150-160, K @ 152 (G) 94 0.87 + 0.06 >25                        XMP.295P (128) 150-158, K @ 152 (G) NT 3.69 + 0.12 >25                        XMP.303P (136) 153-160 98 11.79 + 0.85 NA                                     XMP.327P (160) K-K-153-157-K-K 94 11.92 + 0.09 NA                             XMP.330 (161) 153-156 95 >50 NA                                               XMP.331P (162) $ K-K-153-157-K-K 96 14.11 + 0.35 NA                           XMP.332P (163) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D -                                        98 5.65 + 0.16 NA                               W.sub.D -K.sub.D -K.sub.D                                                    XMP.333P (164) K.sub.D -K-153-157-K-K 98 >25 NA                               XMP.334P (165) P.sub.D -K-K-153-157-K- 89 NA NA                                K                                                                            XMP.335P (166) P-K-153-157-K-K 98 NA NA                                       XMP.336P (167) R-R-153-157-R-R 97 NA NA                                       XMP.337P (168) H-H-153-157-H-H 94 >50 NA                                      XMP.338 (169) ORN-ORN-153-157- 74 >25 NA                                       ORN-ORN                                                                      XMP.339P (170) DAB-DAB-153-157- 98 NA NA                                       DAB-DAB                                                                      XMP.340P (171) p-amino-F-p-amino-F-153- 94 >50 NA                              157-p-amino-F-                                                                amino-F                                                                      XMP.341P (172) PYR-PYR-153-157- 99 >50/ NA/NA                                  PYR-PYR  >50                                                                 XMP.342 (173) K.sub.D -K.sub.D -153-157-K.sub.D - 72 >50 NA                    K.sub.D                                                                      XMP.342P (173) K.sub.D -K.sub.D -153-157-K.sub.D - 97 NA NA                    K.sub.D                                                                      XMP.344P (175) K-K-153-157-K-K, 96 >25 NA                                      A @ 154 (L)                                                                  XMP.345P (176) K-K-153-157-K-K, 93 >50 NA                                      A @ 157 (L)                                                                  XMP.347P (178) K-K-153-157-K-K, 97 1.65 + 0.09 >25                             β(2-naphthyl) A.sub.D @ 153 (W),                                         L @ 156 (Q)                                                                  XMP.348P (179) K-K-K-153-157-K- 97                                             K                                                                            XMP.351P (182) K-K-153-158-K-K 98 8.47 + 0.71 NA                              XMP.352P (183) K-K-153-161 98 2.34 + 0.38 NA                                  XMP.353P (184) P-153-161* 99 4.42 + 0.56 NA                                   XMP.355P (186) P-153-161 99 1.08 + 0.05 NA                                    XMP.356P (187) $ P-153-161 >99 2.72 + 0.02 >25                                XMP.359P (190) C.sub.D -153-161 96 7.31 + 1.26 >25                            XMP.361P (192) K.sub.D -C-154-158-C-K.sub.D 96 >25 NA                         XMP.362P (193) K.sub.D -K-C-154-158-C- 98 >50 NA                               K-K.sub.D                                                                    XMP.363P (194) K.sub.D -W.sub.D -154-159-K.sub.D - 97 >50 NA                   K.sub.D                                                                      XMP.364P (195) $ K.sub.D -W.sub.D -154-159-K.sub.D - 98 >25 NA                 K.sub.D                                                                      XMP.365P (196) K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D -L.sub.D -                                        97 0.52 + 0.07 >25                              F.sub.D -H.sub.D -K.sub.D -K.sub.D                                           XMP.366P (197) $ K.sub.D -W.sub.D -L.sub.D -I.sub.D -Q.sub.D - 99 3.44                                       + 0.90 18.28 + 2.57                             L.sub.D -F.sub.D -H.sub.D -                                                  XMP.367P (198) K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D -Q.sub.D -                                        99 1.35 + 0.03 21.60 + 0.34                     I.sub.D -L.sub.D -W.sub.D -K.sub.D                                           XMP.368P (199) $ K.sub.D -K.sub.D -H.sub.D -F.sub.D -L.sub.D - 93 1.95                                       + 0.11 >25                                      Q.sub.D -I.sub.D -L.sub.D -                                                  XMP.369P (200) 152-161, K @ 152 (G), ORN 95 12.09 + 0.43 NA                    @ 156 (Q)                                                                    XMP.370P (201) $ 152-161, K @ 152 (G), >99 NA >25                              ORN @ 156 (Q)                                                                XMP.371P (202) 152-161, K @ 152 (G), 97 NA NA                                  DAB @ 156 (Q)                                                                XMP.372P (203) $ 152-161, K @ 152 (G), 99 >25 >25                              DAB @ 156 (Q)                                                                XMP.373P (204) $ 152-161, K @ 152 (G) 98 12.79 + 0.19 >25                     XMP.374P (205) K.sub.D -L.sub.D -Q.sub.D -I.sub.D -L.sub.D -W.sub.D -                                        97 13.97 + 2.02 NA                              K.sub.D -K.sub.D                                                             XMP.375P (206) K.sub.D -K.sub.D -W.sub.D -A.sub.D -I.sub.D -Q.sub.D -                                        95 >50 NA                                       L.sub.D -K.sub.D -K.sub.D                                                    XMP.376P (207) K.sub.D -K.sub.D -L.sub.D -Q.sub.D -I.sub.D -A.sub.D -                                        92 >50 NA                                       W.sub.D -K.sub.D -K.sub.D                                                    XMP.377P (208) K-K-K-W-A-I-Q- 97 NA NA                                         L-K-K                                                                        XMP.378P (209) P-W-A-I-Q-L-K- 97 NA NA                                         K                                                                            XMP.379P (210) K-K-P-W-A-I-Q- 98 NA NA                                         L-K-K                                                                        XMP.380P (211) K-K-Q-L-L-L-L- 99 NA NA                                         K-K                                                                          XMP.381P (212) K-K-L-Q-L-L-L- 99 NA NA                                         K-K                                                                          XMP.382P (213) K-K-L-L-Q-L-L- 99 NA NA                                         K-K                                                                          XMP.383P (214) K-K-L-L-L-Q-L- 99 NA NA                                         K-K                                                                          XMP.384P (215) K-K-L-L-L-L-Q 99 NA NA                                          K-K                                                                          XMP.385P (216) K-K-L-L-L-L-L- 99 2.56 + 0.23 >25                               K-K                                                                          XMP.386P (217) 152-161, K @ 152 (G), A 97 9.75 + 1.02 NA                       @ 154 (L)                                                                    XMP.387P (218) 152-161, P @ 152 (G), A @  15.53 + 2.18 NA                      154 (L)                                                                      XMP.388P (219) 152-161 97 8.08 + 1.52 NA                                      XMP.389P (220) 151-161, K @ 151 (V) 99 1.78 + 0.09 NA                         XMP.390P (221) 151-161, K @ 151 (V), P @  3.97 + 0.21 NA                       152 (G)                                                                      XMP.391P (222) 150-161 97 1.49 + 0.02 NA                                      XMP.392P (223) 150-161, P @ 152 (G) 98 24.03 + 2.67 NA                        XMP.393P (224) 148-161, P @ 152 (G)  >25 NA                                   XMP.406P (237) 147-161, P @ 147 (S), A @ 99 >50 NA                             153 (W)                                                                      XMP.407P (238) 147-162, P @ 147 (S), A @ 96 NA NA                              153 (W), D @ 162 (I)                                                         XMP.408P (239) L-K-K-K-W-A-I-  NA NA                                           Q (cyclized head to tail)                                                    XMP.409P (240) S-K-153-157-K-K, A 98 NA NA                                     @ 154 (L)                                                                    XMP.410 CH.sub.3 --(CH.sub.2).sub.6 --CO-- 95 >25 NA                           XMP.344                                                                      XMP.411 CH.sub.3 --(CH.sub.2).sub.10 --CO--  2.94 + 0.14 >25                   XMP.344                                                                      XMP.414 CH.sub.3 --(CH.sub.2).sub.6 --CO--  1.91 + 0.04 10.96 + 0.52                                           XMP.365                                      XMP.415 CH.sub.3 --(CH.sub.2).sub.10 --CO--  1.61 + 0.03 6.80 + 0.14                                           XMP.365                                      XMP.416 NH.sub.2 --(CH.sub.2).sub.7 --CO--  4.67 + 0.27 24.41 + 0.78                                           XMP.365                                      XMP.417 NH.sub.2 --(CH.sub.2).sub.11 --CO--  3.88 + 0.20 11.26 + 1.30                                          XMP.365                                    __________________________________________________________________________     .sup.a NA for EC.sub.50 means no evidence neutralization of LPS at up to      50 μg/ml                                                                   .sup.b NA for IC.sub.50 means no evidence of decreased RAW cell growth at     up to 50 μg/ml                                                             .sup.c NT = not tested                                                   

Domain III derived peptides are also tested for LPS neutralizingefficacy in an in vivo mouse experimental endotoxemia model. Groups of15 mice were administered an intravenous injection of endotoxin (E. coli0111:B4, Sigma Chemical Co., St. Louis, Mo.) at a LD₉₀ dosage of 20mg/kg. This was followed by a second intravenous injection of thepeptide to be tested. Injections of saline were used in negative controlmice. The animals were observed for 7 days and mortality recorded. Theefficacy of the peptides was measured by a decrease inendotoxemia-associated mortality in peptide-injected mice as comparedwith control mice. XMP.284 is a representative peptide active in thismurine model. As shown in FIG. 9, significant protection was observedwith a 0.5 mg/kg dose of XM-P.284, while at a 1 mg/kg dose, 14 of 15animals were protected, and a 3 mg/kg dose was effective to protect alltreated animals (100% survival). No animals survived in the salinecontrol group.

EXAMPLE 8 Peptide Formulations

This example addresses peptide formulations. A representative Domain IIIderived peptide XMP.284 was evaluated for stability in liquidformulations containing buffered saline solutions and to elucidatebreakdown mechanisms, if any, that might be common to such peptides.

The lyophilized peptide was dissolved to a concentration of 1 mg/mL inthree different buffers. The three formulation buffers used were (a) 10mM solution acetate, 150 mM sodium chloride pH 4, (b) 10 mM sodiumacetate, 150 mM sodium chloride pH 5 and (c) 10 mM sodium acetate, 150mM sodium chloride pH 6. The formulated peptide samples were incubatedat 4° C. and 37° C. At each time point, samples were withdrawn from eachvial and assayed by C18 reverse phase HPLC, absorbance at 280 nm, andSDS-PAGE. The study was conducted for 50 days.

A 0.46×25 cm Vydac C18 column (cat no. 218TP54) was used on a ShimadzuHPLC system. The column was run in binary gradient mobile phases:A=Water+0.05% TFA, B=acetonitrile+0.05% TFA. Chromatographic conditionswere as follows: wavelength=229 nm; flowrate=1 mL/min; injectionvolume=50 μL; run time=37 minutes; gradient=20% B to 40% B in 20minutes; AUFS =0.1 for P.284; concentration of sample=3.5 μg per 50 μLinjection volume. In preparation for the C18 assay, the sampleswithdrawn from the vials were diluted 16-fold with 0.05% TFA in water.All samples were filtered through Acrodisc 4 prior to analysis.

Samples were analyzed by SDS polyacrylamide gel electrophoresis, run onNovex 10-20% tricine precast gels (Novex, La Jolla, Calif., EC6625).Samples were mixed with non-reducing sample loading buffer (NovexLC1676, 2x) and heated at 95° C. for two minutes. After cooling, sampleswere run on the gel and the gels were stained with Coomassie Blue. Inaddition, samples were analyzed spectrophotometrically. For this,samples withdrawn at each time point were diluted 6-fold with Milliporewater and absorbance was measured at 280 nm and scanning from 210 nm to340 nm using a Shimadzu UV 160 spectrophotometer. All samples werefiltered prior to absorbance measurement(s).

XMLP.284 was soluble in water and unbuffered saline. XMP.284 was alsosoluble in 10 mM sodium phosphate, 150 mM sodium chloride pH 7. Thepeptide remained soluble in the phosphate buffer at 40° C. for 1 hourand then 55° C. for 1 hour. There was very little product loss, asmeasured by absorbance at 280 nm, in 0.15 M saline buffered with 10 mMacetate at pH 4, 5 or 6. The real time stability study at 4° C. showedthat product concentration was unchanged. Even the accelerated stabilitystudy at 37° C. showed that greater than 95% of product concentrationwas maintained and that only low levels (less than 0.5% at 50 days) ofnew HPLC peaks accumulated with time at 37° C. in the acetate bufferedsaline formulations. Given the substantial stability exhibited by theDomain III derived peptide as tested, additional excipients may not benecessary but may be desired to further enhance long-term stabilityand/or activity. Presently preferred is a formulation that includes 10mM sodium acetate, 150 mM sodium chloride, pH5.

Numerous modifications and variations in the practice of the inventionare expected to occur to those skilled in the art upon consideration ofthe foregoing description on the presently preferred embodimentsthereof. Consequently the only limitations which should be placed uponthe scope of the present invention are those that appear in the appendedclaims.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 252                                         - -  - - (2) INFORMATION FOR SEQ ID NO:1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 22 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.5"                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                               - - Val His Val His Ile Ser Lys Ser Lys Val Gl - #y Trp Leu Ile Gln        Leu                                                                             1               5   - #                10  - #                15              - - Phe His Lys Lys Ile Glu                                                              20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.11"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                               - - Lys Ser Lys Val Trp Leu Ile Gln Leu Phe Hi - #s Lys Lys                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.12"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                               - - Ser Val His Val His Ile Ser Lys Ser Lys Va - #l Gly Trp Leu Ile Gln      1               5   - #                10  - #                15               - - Leu Phe His Lys Lys Ile Glu Ser Ala Leu Ar - #g Asn Lys                              20      - #             25                                         - -  - - (2) INFORMATION FOR SEQ ID NO:4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.13"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                               - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.29"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                               - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Gln Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.31"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                               - - Ala Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.32"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                               - - Lys Ala Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.33"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                               - - Lys Ser Ala Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.34"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                               - - Lys Ser Lys Ala Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.35"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                              - - Lys Ser Lys Val Ala Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.36"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.37"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                              - - Lys Ser Lys Val Gly Trp Ala Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.38"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                              - - Lys Ser Lys Val Gly Trp Leu Ala Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.39"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                              - - Lys Ser Lys Val Gly Trp Leu Ile Ala Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:15:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.40"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:16:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.41"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Al - #a His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:17:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.42"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:18:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.43"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Ala Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:19:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.44"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:20:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.55"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                              - - Gly Trp Leu Ile Gln Leu Phe His Lys Lys Il - #e Glu Ser Ala Leu Arg      1               5   - #                10  - #                15               - - Asn Lys Met Asn Ser                                                                  20                                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:21:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.82"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:22:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.83"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted"                                - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:23:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.85"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                              - - Lys Ser Lys Val Leu Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:24:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.86"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                              - - Lys Ser Lys Val Gly Trp Leu Ile Leu Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:25:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.87"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Leu Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:26:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.91"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:27:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.92"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                              - - Lys Ser Lys Val Gly Trp Leu Ile Lys Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:28:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.94"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Phe Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:29:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.95"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:30:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.96"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Phe              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:31:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.97"                                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                              - - Lys Ser Lys Val Lys Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:32:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.100"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                              - - Lys Ser Lys Val Lys Trp Leu Ile Lys Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:33:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.101"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                              - - Lys Ser Lys Val Lys Trp Leu Ile Lys Leu Ph - #e Phe Lys Phe Lys Ser      1               5   - #                10  - #                15               - - Lys Val Lys Trp Leu Ile Lys Leu Phe Phe Ly - #s Phe                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:34:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.104"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                              - - Lys Ser Lys Val Gly Trp Leu Ile Ser Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:35:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.106"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                              - - Lys Ser Lys Val Gly Trp Leu Ile Thr Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:36:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.107"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Trp Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:37:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.108"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Trp              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:38:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.109"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 11 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Al - #a His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:39:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.110"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:40:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.111"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 14 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:41:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.113"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Phe Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:42:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.116"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                              - - Lys Ser Lys Val Lys Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:43:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.123"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"The phenylalanine at position 9 is                                 p-amino-subs - #tituted."                                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:44:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.124"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                              - - Lys Ser Lys Val Lys Trp Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:45:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.125"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                              - - Lys Ser Lys Val Gly Trp Leu Ile Tyr Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:46:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.126"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= D-Trp                                            /note= - #"Position 6 is D-tryptophan."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:47:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.127"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                              - - Lys Ser Lys Val Gly Phe Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:48:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.128"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= D-Phe                                            /note= - #"Position 6 is D-phenylalanine."                      - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                              - - Lys Ser Lys Val Gly Phe Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:49:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.129"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      D-1-beta-1-n - #aphthyl-substituted."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:50:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.130"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-2-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:51:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.131"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      D-beta-2-nap - #hthyl-substituted."                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:52:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.132"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"The alanine at position 6 is                                       pyridyl-subs - #tituted."                                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:53:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.133"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 6 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                              - - Lys Ser Lys Val Gly Phe Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:54:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.134"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:55:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.135"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                              - - Lys Ser Lys Val Gly Lys Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:56:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                               - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.137"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                              - - Cys Lys Ser Lys Val Gly Trp Leu Ile Gln Le - #u Phe His Lys Lys Cys      1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO:57:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.138"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                              - - Lys Ser Lys Val Lys Phe Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:58:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.139"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                              - - Lys Ser Lys Val Gly Tyr Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:59:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.142"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Trp Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:60:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.143"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:61:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.144"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"The alanine at position 6 is                                       cyclohexyl-s - #ubstituted."                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:62:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.146"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 14 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e Ala Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:63:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.148"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:64:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.161"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                              - - Lys Ser Lys Val Lys Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:65:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.166"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                              - - Lys Ser Lys Val Gly Val Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:66:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.222"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6 & 14                                                          (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Positions 6 and 14 are                                             beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:67:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.223"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6 & 10                                                          (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Positions 6 & 10 are                                               beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:68:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.224"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                              - - Lys Ser Lys Val Gly Ala Leu Ile Phe Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:69:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.225"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                              - - Lys Ser Lys Val Phe Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:70:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.226"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:71:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.227"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10 & 1 - #4                                                     (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Positions 10 & 14 are                                              beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Ala Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:72:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.228"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 14 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:73:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.229"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 14 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Ph - #e His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:74:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.230"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 14 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Tr - #p His Lys Ala              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:75:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.231"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10 & 1 - #2                                                     (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Positions 10 & 12 are                                              beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Ala Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:76:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.232"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:77:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.233"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Ph - #e Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:78:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.234"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 12 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Tr - #p Ala Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:79:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.235"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:80:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.236"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:81:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.237"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                              - - Lys Ser Lys Val Gly Trp Leu Ile Gln Ala Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:82:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.238"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                              - - Lys Ser Lys Val Phe Trp Leu Ile Phe Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:83:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.239"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 9 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                              - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:84:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.240"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                              - - Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:85:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.241"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                              - - Lys Ser Lys Val Gly Trp Leu Ile Leu Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:86:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.242"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      D-beta-2-nap - #hthyl-substituted."                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                              - - Lys Ser Lys Val Gly Ala Leu Ile Leu Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:87:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.243"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      D-beta-2-nap - #hthyl-substituted."                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:88:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.244"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      D-beta-2-nap - #hthyl-substituted."                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                              - - Lys Ser Lys Val Gly Ala Leu Ile Leu Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:89:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.249"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                              - - Lys Ser Lys Val Gly Gly Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:90:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.250"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                              - - Lys Ser Lys Val Gly Leu Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:91:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.251"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                              - - Lys Ser Lys Val Gly Ile Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:92:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.252"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= D-Ala                                            /note= - #"Position 6 is D-alanine"                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:93:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.253"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= D-Val                                            /note= - #"Position 6 is D-valine"                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                              - - Lys Ser Lys Val Gly Val Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:94:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.254"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= beta-Ala                                         /note= - #"Position 6 is beta-alanine"                          - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:95:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.255"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= alpha-aba                                        /note= - #"Position 6 is alpha-aminobutyric acid"               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                              - - Lys Ser Lys Val Gly Xaa Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:96:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.256"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= gaba                                             /note= - #"Position 6 is gamma-aminobutyric acid"               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                              - - Lys Ser Lys Val Gly Xaa Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:97:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.257"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= `-methyl-A                                       /note= - #"Position 6 is alpha-Methyl-alanine"                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                              - - Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:98:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.258"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= t-butyl-G                                        /note= - #"Position 6 is tert-butyl-glycine"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                              - - Lys Ser Lys Val Gly Gly Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:99:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.259"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= N-methyl-G                                       /note= - #"Position 6 is N-Methyl-glycine"                      - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                              - - Lys Ser Lys Val Gly Gly Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:100:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.260"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= N-methyl-V                                       /note= - #"Position 6 is N-Methyl-valine"                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                             - - Lys Ser Lys Val Gly Val Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:101:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.261"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (D) OTHER INFORMATION: - #/label= N-methyl-L                                       /note= - #"Position 6 is N-Methyl-leucine"                      - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                             - - Lys Ser Lys Val Gly Leu Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:102:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.262"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                             - - Lys Ser Lys Val Gly Trp Leu Ile Asn Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:103:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.263"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                             - - Lys Ser Lys Val Gly Trp Leu Ile Glu Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:104:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.264"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                             - - Lys Ser Lys Val Gly Trp Leu Ile Asp Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:105:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.265"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                             - - Lys Ser Lys Val Gly Trp Leu Ile Arg Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:106:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.266"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                             - - Lys Ser Lys Val Lys Val Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:107:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.267"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                             - - Lys Ser Lys Val Lys Trp Ala Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:108:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.268"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                             - - Lys Ser Lys Val Gly Val Ala Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:109:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.269"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                             - - Lys Ser Lys Val Lys Val Ala Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:110:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.270"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                             - - Lys Ser Lys Val Gly Trp Leu Ile Leu Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Gln Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:111:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.271"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                             - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Leu Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:112:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.272"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                             - - Lys Ser Lys Val Gly Trp Leu Ile Leu Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Leu Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:113:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.273"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                             - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Gln Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:114:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.274"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                             - - Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Phe Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:115:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 28 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.275"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                             - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Ph - #e His Lys Lys Lys Ser      1               5   - #                10  - #                15               - - Lys Val Gly Trp Leu Ile Phe Leu Phe His Ly - #s Lys                                  20      - #            25                                          - -  - - (2) INFORMATION FOR SEQ ID NO:116:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.283"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                             - - Lys Ser Lys Val Lys Phe Leu Ile Lys Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:117:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.284"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                             - - Ser Lys Val Lys Trp Leu Ile Gln Leu Phe Hi - #s Lys Lys                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:118:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.285"                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                             - - Ser Lys Val Lys Trp Leu Ile Gln Leu Phe Hi - #s Lys                      1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:119:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.286"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                             - - Lys Val Lys Trp Leu Ile Gln Leu Phe His Ly - #s Lys                      1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:120:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.287"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                             - - Ser Lys Val Lys Trp Leu Ile Gln Leu Phe Hi - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:121:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.288"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                             - - Lys Val Lys Trp Leu Ile Gln Leu Phe His Ly - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:122:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.289"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                             - - Val Lys Trp Leu Ile Gln Leu Phe His Lys Ly - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:123:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.290"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                             - - Ser Lys Val Lys Trp Leu Ile Gln Leu Phe                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:124:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.291"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                             - - Lys Val Lys Trp Leu Ile Gln Leu Phe His                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:125:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.292"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                             - - Val Lys Trp Leu Ile Gln Leu Phe His Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:126:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.293"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:127:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.294"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                             - - Ser Lys Val Lys Trp Leu Ile Gln Leu                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:128:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.295"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                             - - Lys Val Lys Trp Leu Ile Gln Leu Phe                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:129:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.296"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                             - - Val Lys Trp Leu Ile Gln Leu Phe His                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:130:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.297"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:131:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.298"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                             - - Trp Leu Ile Gln Leu Phe His Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:132:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.299"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                             - - Ser Lys Val Lys Trp Leu Ile Gln                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:133:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.300"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                             - - Lys Val Lys Trp Leu Ile Gln Leu                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:134:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.301"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                             - - Val Lys Trp Leu Ile Gln Leu Phe                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:135:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.302"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                             - - Lys Trp Leu Ile Gln Leu Phe His                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:136:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.303"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                             - - Trp Leu Ile Gln Leu Phe His Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:137:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.304"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                             - - Leu Ile Gln Leu Phe His Lys Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:138:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.305"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                             - - Ser Lys Val Lys Trp Leu Ile                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:139:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.306"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                             - - Lys Val Lys Trp Leu Ile Gln                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:140:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.307"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                             - - Val Lys Trp Leu Ile Gln Leu                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:141:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.308"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                             - - Lys Trp Leu Ile Gln Leu Phe                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:142:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.309"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                             - - Trp Leu Ile Gln Leu Phe His                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:143:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.310"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                             - - Leu Ile Gln Leu Phe His Lys                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:144:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.311"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                             - - Ile Gln Leu Phe His Lys Lys                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:145:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.312"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                             - - Ser Lys Val Lys Trp Leu                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:146:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.313"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                             - - Lys Val Lys Trp Leu Ile                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:147:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.314"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                             - - Val Lys Trp Leu Ile Gln                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:148:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.315"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                             - - Lys Trp Leu Ile Gln Leu                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:149:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.316"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                             - - Trp Leu Ile Gln Leu Phe                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:150:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.317"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                             - - Leu Ile Gln Leu Phe His                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:151:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.318"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                             - - Ile Gln Leu Phe His Lys                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:152:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.319"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                             - - Gln Leu Phe His Lys Lys                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:153:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.320"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                             - - Trp Leu Ile Gln Leu                                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:154:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.321"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:                             - - Trp Leu Ile Gln Leu Lys                                                  1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:155:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.322"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:                             - - Trp Leu Ile Gln Leu Lys Lys                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:156:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.323"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:                             - - Lys Trp Leu Ile Gln Leu Lys                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:157:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.324"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:                             - - Lys Trp Leu Ile Gln Leu Lys Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:158:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.325"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:                             - - Lys Lys Trp Leu Ile Gln Leu                                              1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:159:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.326"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:                             - - Lys Lys Trp Leu Ile Gln Leu Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:160:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.327"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:                             - - Lys Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:161:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.330"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:                             - - Trp Leu Ile Gln                                                          1                                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:162:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.331"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:                             - - Lys Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:163:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.332"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-9                                                             (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-9 are D-amino acids"                     - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:                             - - Lys Lys Leu Gln Ile Leu Trp Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:164:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.333"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Position 1 is D-lysine"                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:                             - - Lys Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:165:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.334"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= D-Pro                                            /note= - #"Position 1 is D-proline"                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:                             - - Pro Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:166:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.335"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:                             - - Pro Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:167:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.336"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:                             - - Arg Arg Trp Leu Ile Gln Leu Arg Arg                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:168:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.337"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:                             - - His His Trp Leu Ile Gln Leu His His                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:169:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.338"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 2, - #8 & 9                                                  (D) OTHER INFORMATION: - #/label= Orn                                              /note= - #"Positions 1, 2, 8 & 9 are Ornithine"                 - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:                             - - Xaa Xaa Trp Leu Ile Gln Leu Xaa Xaa                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:170:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.339"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 2, - #8 & 9                                                  (D) OTHER INFORMATION: - #/label= Dbu                                              /note= - #"Positions 1, 2, 8 & 9 are Diaminobutyric                           acid"                                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:                             - - Xaa Xaa Trp Leu Ile Gln Leu Xaa Xaa                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:171:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.340"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 2, - #8 & 9                                                  (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Positions 1, 2, 8 & 9 are                                          para-amino-s - #ubstituted."                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:                             - - Phe Phe Trp Leu Ile Gln Leu Phe Phe                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:172:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.341"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 2, - #8 & 9                                                  (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"The alanine at positions 1, 2, 8 & 9 is                            pyridyl-subs - #tituted."                                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:                             - - Ala Ala Trp Leu Ile Gln Leu Ala Ala                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:173:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.342"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 2, - #8 & 9                                                  (D) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1, 2, 8 & 9 are D-lysine"                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:                             - - Lys Lys Trp Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:174:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.343"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:                             - - Lys Lys Val Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:175:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.344"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:                             - - Lys Lys Trp Ala Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:176:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.345"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:                             - - Lys Lys Trp Leu Ile Gln Ala Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:177:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.346"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"The phenylalanine at position 3 is                                 p-amino-subs - #tituted."                                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:                             - - Lys Lys Phe Leu Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:178:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.347"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 3 is                                                      D-beta-2-nap - #hthyl-substituted."                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:                             - - Lys Lys Ala Leu Ile Leu Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:179:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.348"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:                             - - Lys Lys Lys Trp Leu Ile Gln Leu Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:180:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.349"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:                             - - Lys Lys Trp Leu Ile Gln Leu Lys Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:181:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.350"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:                             - - Lys Lys Lys Trp Leu Ile Gln Leu Lys Lys Ly - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:182:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.351"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:                             - - Lys Lys Trp Leu Ile Gln Leu Phe Lys Lys                                  1                5  - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:183:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.352"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:                             - - Lys Lys Trp Leu Ile Gln Leu Phe His Lys Ly - #s                          1                5  - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:184:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.353"                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:                             - - Pro Trp Leu Ile Gln Leu Phe His Lys Lys                                  1                5  - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:185:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.354"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:                             - - Pro Trp Leu Ile Gln Leu Phe His Lys Lys                                  1                5  - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:186:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.355"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:                             - - Pro Trp Leu Ile Gln Leu Phe His Lys Lys                                  1                5  - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:187:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.356"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:                             - - Pro Trp Leu Ile Gln Leu Phe His Lys Lys                                  1                5  - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:188:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.357"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Pro                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:189:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.358"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:                             - - Lys Lys Trp Leu Ile Gln Leu Phe His Lys Pr - #o                          1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:190:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.359"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (C) OTHER INFORMATION: - #/label= D-Cys                                            /note= - #"Position 1 is D-cysteine."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:                             - - Cys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:191:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                               - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.360"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1 & 9                                                           (C) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1 & 9 are D-lysine."                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                               (C) OTHER INFORMATION: - #/label= D-Cys                                            /note= - #"Position 2 is D-cysteine."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:                             - - Lys Cys Leu Ile Gln Leu Phe Cys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:192:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                               - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.361"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1 & 9                                                           (C) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1 & 9 are D-lysine."                       - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:                             - - Lys Cys Leu Ile Gln Leu Phe Cys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:193:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                               - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.362"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1 & 11                                                          (C) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1 & 11 are D-lysine."                      - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:                             - - Lys Lys Cys Leu Ile Gln Leu Phe Cys Lys Ly - #s                          1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:194:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.363"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 9 & - # 10                                                   (C) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1, 9 & 10 are D-lysine."                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                               (C) OTHER INFORMATION: - #/label= D-Trp                                            /note= - #"Position 2 is D-tryptophan."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:195:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.364"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1, 9 & - # 10                                                   (C) OTHER INFORMATION: - #/label= D-Lys                                            /note= - #"Positions 1, 9 & 10 are D-lysine."                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                               (C) OTHER INFORMATION: - #/label= D-Trp                                            /note= - #"Position 2 is D-tryptophan."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:195:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:196:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.365"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:196:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:197:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.366"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:197:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:198:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.367"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:198:                             - - Lys Lys His Phe Leu Gln Ile Leu Trp Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:199:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.368"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:199:                             - - Lys Lys His Phe Leu Gln Ile Leu Trp Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:200:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.369"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (D) OTHER INFORMATION: - #/label= Orn                                              /note= - #"Position 5 is Ornithine"                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:200:                             - - Lys Trp Leu Ile Xaa Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:201:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.370"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (D) OTHER INFORMATION: - #/label= Orn                                              /note= - #"Position 5 is Ornithine"                             - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:201:                             - - Lys Trp Leu Ile Xaa Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:202:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.371"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (D) OTHER INFORMATION: - #/label= Dbu                                              /note= - #"Position 5 is Diaminobutyric acid"                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:202:                             - - Lys Trp Leu Ile Xaa Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:203:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.372"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (D) OTHER INFORMATION: - #/label= Dbu                                              /note= - #"Position 5 is Diaminobutyric acid"                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:203:                             - - Lys Trp Leu Ile Xaa Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:204:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.373"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                               (D) OTHER INFORMATION: - #/label= Acetylated                                       /note= - #"Position 1 is acetylated."                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:204:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:205:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.374"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-8                                                             (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-8 are D-Amino Acids."                    - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:205:                             - - Lys Leu Gln Ile Leu Trp Lys Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:206:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.375"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-9                                                             (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-9 are D-Amino Acids."                    - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:206:                             - - Lys Lys Trp Ala Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:207:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.376"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-9                                                             (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-9 are D-Amino Acids."                    - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:207:                             - - Lys Lys Leu Gln Ile Ala Trp Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:208:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.377"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:208:                             - - Lys Lys Lys Trp Ala Ile Gln Leu Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:209:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.378"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:209:                             - - Pro Trp Ala Ile Gln Leu Lys Lys                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:210:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.379"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:210:                             - - Lys Lys Pro Trp Ala Ile Gln Leu Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:211:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.380"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:211:                             - - Lys Lys Gln Leu Leu Leu Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:212:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.381"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:212:                             - - Lys Lys Leu Gln Leu Leu Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:213:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.382:                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:213:                             - - Lys Lys Leu Leu Gln Leu Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:214:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.383"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:214:                             - - Lys Lys Leu Leu Leu Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:215:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.384"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:215:                             - - Lys Lys Leu Leu Leu Leu Gln Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:216:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.385"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:216:                             - - Lys Lys Leu Leu Leu Leu Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:217:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.386"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:217:                             - - Lys Trp Ala Ile Gln Leu Phe His Lys Lys Il - #e                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:218:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.387"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:218:                             - - Pro Trp Ala Ile Gln Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:219:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.388"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:219:                             - - Gly Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:220:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.389"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:220:                             - - Lys Gly Trp Leu Ile Gln Leu Phe His Lys Ly - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:221:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.390"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:221:                             - - Lys Pro Trp Leu Ile Gln Leu Phe His Lys Ly - #s                          1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:222:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.391"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:222:                             - - Lys Val Gly Trp Leu Ile Gln Leu Phe His Ly - #s Lys                      1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:223:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.392"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:223:                             - - Lys Val Pro Trp Leu Ile Gln Leu Phe His Ly - #s Lys                      1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:224:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.393"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:224:                             - - Lys Ser Lys Val Pro Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:225:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.394"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-15                                                            (C) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-15 are D-Amino Acids."                   - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5 & 9                                                           (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note="- #Positions 5 & 9 are                                                 beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:225:                             - - Lys Leu Phe Arg Ala Gln Ala Lys Ala Lys Gl - #y Ser Ile Lys Ile          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO:226:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.395"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note="- #Position 6 is beta-1-naphthyl-substituted."           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:226:                             - - Lys Ser Lys Val Gly Ala Leu Ile Leu Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:227:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.396"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note="- #Position 6 is beta-1-naphthyl-substituted."           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:227:                             - - Lys Ser Lys Val Gly Ala Leu Ile Phe Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:228:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.397"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                               (C) OTHER INFORMATION: - #/label= Substituted-Phe                                  /note= - #"Position 5 is para-amino-substituted."               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note="- #Position 6 is beta-1-naphthyl-substituted."           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:228:                             - - Lys Ser Lys Val Phe Ala Leu Ile Gln Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:229:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.398"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     D-beta-1-nap - #hthyl-substituted."                             - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:229:                             - - Lys Ser Lys Val Gly Trp Leu Ile Leu Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:230:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.399"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:230:                             - - Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:231:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.400"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:231:                             - - Lys Ser Lys Val Gly Ala Leu Ile Leu Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:232:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.401"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:232:                             - - Lys Ser Lys Val Gly Trp Leu Ile Phe Ala Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:233:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.402"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                               (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 is                                                      beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:233:                             - - Lys Ser Lys Val Gly Ala Leu Ile Phe Leu Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:234:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.403"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6 & 10                                                          (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 6 & 10 is                                                 beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:234:                             - - Lys Ser Lys Val Gly Ala Leu Ile Gln Ala Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:235:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.404"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:235:                             - - Lys Ser Lys Val Gly Trp Leu Ile Phe Ala Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:236:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.405"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                              (C) OTHER INFORMATION: - #/label= Substituted-Ala                                  /note= - #"Position 10 is                                                     beta-1-napht - #hyl-substituted."                               - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:236:                             - - Lys Ser Lys Val Gly Trp Leu Ile Leu Ala Tr - #p His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:237:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.406"                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:237:                             - - Pro Lys Ser Lys Val Gly Ala Leu Ile Gln Le - #u Phe His Lys Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO:238:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.407"                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:238:                             - - Pro Lys Ser Lys Val Gly Ala Leu Ile Gln Le - #u Phe His Lys Lys Asp      1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO:239:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.408"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"Peptide is Cyclized Head to Tail"         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:239:                             - - Leu Lys Lys Lys Trp Ala Ile Gln                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:240:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.409"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:240:                             - - Ser Lys Trp Ala Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:241:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.410"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= caprylyl group                                   /note= - #"CH3-(CH2)6-CO at N-Terminus."                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:241:                             - - Lys Lys Trp Ala Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:242:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.411"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= lauryl group                                     /note= - #"CH3-(CH2)10-CO at N-Terminus."                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:242:                             - - Lys Lys Trp Ala Ile Gln Leu Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:243:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.412"                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:243:                             - - Leu Lys Lys Lys Trp Ala Ile Gln                                          1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:244:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.414"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= caprylyl group                                   /note= - #"CH3-(CH2)6-CO at N-Terminus."                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:244:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:245:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.415"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= lauryl group                                     /note= - #"CH3-(CH2)10-CO at N-Terminus."                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:245:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:246:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.416"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= 8-amino-octanyl group                            /note= - #"NH2-(CH2)7-CO at N-Terminus."                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:246:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:247:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.417"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label= 12-amino-dodecanyl group                         /note= - #"NH2-(CH2)11-CO at N-Terminus."                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:247:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:248:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.418"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:248:                             - - Lys Ser Lys Val Pro Trp Leu Ile Gln Leu Ph - #e His Lys Lys              1               5   - #                10                                      - -  - - (2) INFORMATION FOR SEQ ID NO:249:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.419"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-9                                                             (C) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-9 are D-Amino Acids."                    - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:249:                             - - Lys Trp Leu Ile Leu Phe His Lys Lys                                      1               5                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:250:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.420"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: C-Terminus                                                      (D) OTHER INFORMATION: - #/label= Amidation                                        /note= - #"The C-Terminus is Amidated."                         - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: N-Terminus                                                      (D) OTHER INFORMATION: - #/label=                                                  /note= - #"The N-Terminus is protected by                                     1-Fluorenylm - #ethyl-                                                        oxycarbonyl - #(Fmoc)"                                          - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"XMP.365"                                  - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1-10                                                            (D) OTHER INFORMATION: - #/label= D-Amino Acids                                    /note= - #"Positions 1-10 are D-amino acids"                    - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:250:                             - - Lys Trp Leu Ile Gln Leu Phe His Lys Lys                                  1               5   - #                 10                                     - -  - - (2) INFORMATION FOR SEQ ID NO:251:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1813 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 31..1491                                               - -     (ix) FEATURE:                                                                  (A) NAME/KEY: mat.sub.-- - #peptide                                           (B) LOCATION: 124..1491                                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: misc.sub.-- - #feature                                          (D) OTHER INFORMATION: - #"rBPI"                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:251:                             - - CAGGCCTTGA GGTTTTGGCA GCTCTGGAGG ATG AGA GAG AAC AT - #G GCC AGG        GGC      54                                                                                       - #               Met Arg - #Glu Asn Met Ala Arg Gly                         - #               -31 -30 - #                -25             - - CCT TGC AAC GCG CCG AGA TGG GTG TCC CTG AT - #G GTG CTC GTC GCC ATA          102                                                                       Pro Cys Asn Ala Pro Arg Trp Val Ser Leu Me - #t Val Leu Val Ala Ile                       -20      - #           -15      - #           -10                  - - GGC ACC GCC GTG ACA GCG GCC GTC AAC CCT GG - #C GTC GTG GTC AGG ATC          150                                                                       Gly Thr Ala Val Thr Ala Ala Val Asn Pro Gl - #y Val Val Val Arg Ile                    -5         - #          1        - #       5                          - - TCC CAG AAG GGC CTG GAC TAC GCC AGC CAG CA - #G GGG ACG GCC GCT CTG          198                                                                       Ser Gln Lys Gly Leu Asp Tyr Ala Ser Gln Gl - #n Gly Thr Ala Ala Leu            10                 - # 15                 - # 20                 - # 25       - - CAG AAG GAG CTG AAG AGG ATC AAG ATT CCT GA - #C TAC TCA GAC AGC TTT          246                                                                       Gln Lys Glu Leu Lys Arg Ile Lys Ile Pro As - #p Tyr Ser Asp Ser Phe                            30 - #                 35 - #                 40              - - AAG ATC AAG CAT CTT GGG AAG GGG CAT TAT AG - #C TTC TAC AGC ATG GAC          294                                                                       Lys Ile Lys His Leu Gly Lys Gly His Tyr Se - #r Phe Tyr Ser Met Asp                        45     - #             50     - #             55                  - - ATC CGT GAA TTC CAG CTT CCC AGT TCC CAG AT - #A AGC ATG GTG CCC AAT          342                                                                       Ile Arg Glu Phe Gln Leu Pro Ser Ser Gln Il - #e Ser Met Val Pro Asn                    60         - #         65         - #         70                      - - GTG GGC CTT AAG TTC TCC ATC AGC AAC GCC AA - #T ATC AAG ATC AGC GGG          390                                                                       Val Gly Leu Lys Phe Ser Ile Ser Asn Ala As - #n Ile Lys Ile Ser Gly                75             - #     80             - #     85                          - - AAA TGG AAG GCA CAA AAG AGA TTC TTA AAA AT - #G AGC GGC AAT TTT GAC          438                                                                       Lys Trp Lys Ala Gln Lys Arg Phe Leu Lys Me - #t Ser Gly Asn Phe Asp            90                 - # 95                 - #100                 - #105       - - CTG AGC ATA GAA GGC ATG TCC ATT TCG GCT GA - #T CTG AAG CTG GGC AGT          486                                                                       Leu Ser Ile Glu Gly Met Ser Ile Ser Ala As - #p Leu Lys Leu Gly Ser                           110  - #               115  - #               120              - - AAC CCC ACG TCA GGC AAG CCC ACC ATC ACC TG - #C TCC AGC TGC AGC AGC          534                                                                       Asn Pro Thr Ser Gly Lys Pro Thr Ile Thr Cy - #s Ser Ser Cys Ser Ser                       125      - #           130      - #           135                  - - CAC ATC AAC AGT GTC CAC GTG CAC ATC TCA AA - #G AGC AAA GTC GGG TGG          582                                                                       His Ile Asn Ser Val His Val His Ile Ser Ly - #s Ser Lys Val Gly Trp                   140          - #       145          - #       150                      - - CTG ATC CAA CTC TTC CAC AAA AAA ATT GAG TC - #T GCG CTT CGA AAC AAG          630                                                                       Leu Ile Gln Leu Phe His Lys Lys Ile Glu Se - #r Ala Leu Arg Asn Lys               155              - #   160              - #   165                          - - ATG AAC AGC CAG GTC TGC GAG AAA GTG ACC AA - #T TCT GTA TCC TCC AAG          678                                                                       Met Asn Ser Gln Val Cys Glu Lys Val Thr As - #n Ser Val Ser Ser Lys           170                 1 - #75                 1 - #80                 1 -      #85                                                                              - - CTG CAA CCT TAT TTC CAG ACT CTG CCA GTA AT - #G ACC AAA ATA GAT        TCT      726                                                                    Leu Gln Pro Tyr Phe Gln Thr Leu Pro Val Me - #t Thr Lys Ile Asp Ser                          190  - #               195  - #               200              - - GTG GCT GGA ATC AAC TAT GGT CTG GTG GCA CC - #T CCA GCA ACC ACG GCT          774                                                                       Val Ala Gly Ile Asn Tyr Gly Leu Val Ala Pr - #o Pro Ala Thr Thr Ala                        205     - #            210     - #            215                 - - GAG ACC CTG GAT GTA CAG ATG AAG GGG GAG TT - #T TAC AGT GAG AAC CAC          822                                                                       Glu Thr Leu Asp Val Gln Met Lys Gly Glu Ph - #e Tyr Ser Glu Asn His                   220          - #       225          - #       230                      - - CAC AAT CCA CCT CCC TTT GCT CCA CCA GTG AT - #G GAG TTT CCC GCT GCC          870                                                                       His Asn Pro Pro Pro Phe Ala Pro Pro Val Me - #t Glu Phe Pro Ala Ala               235              - #   240              - #   245                          - - CAT GAC CGC ATG GTA TAC CTG GGC CTC TCA GA - #C TAC TTC TTC AAC ACA          918                                                                       His Asp Arg Met Val Tyr Leu Gly Leu Ser As - #p Tyr Phe Phe Asn Thr           250                 2 - #55                 2 - #60                 2 -      #65                                                                              - - GCC GGG CTT GTA TAC CAA GAG GCT GGG GTC TT - #G AAG ATG ACC CTT        AGA      966                                                                    Ala Gly Leu Val Tyr Gln Glu Ala Gly Val Le - #u Lys Met Thr Leu Arg                          270  - #               275  - #               280              - - GAT GAC ATG ATT CCA AAG GAG TCC AAA TTT CG - #A CTG ACA ACC AAG TTC         1014                                                                       Asp Asp Met Ile Pro Lys Glu Ser Lys Phe Ar - #g Leu Thr Thr Lys Phe                       285      - #           290      - #           295                  - - TTT GGA ACC TTC CTA CCT GAG GTG GCC AAG AA - #G TTT CCC AAC ATG AAG         1062                                                                       Phe Gly Thr Phe Leu Pro Glu Val Ala Lys Ly - #s Phe Pro Asn Met Lys                   300          - #       305          - #       310                      - - ATA CAG ATC CAT GTC TCA GCC TCC ACC CCG CC - #A CAC CTG TCT GTG CAG         1110                                                                       Ile Gln Ile His Val Ser Ala Ser Thr Pro Pr - #o His Leu Ser Val Gln                315             - #    320             - #    325                         - - CCC ACC GGC CTT ACC TTC TAC CCT GCC GTG GA - #T GTC CAG GCC TTT GCC         1158                                                                       Pro Thr Gly Leu Thr Phe Tyr Pro Ala Val As - #p Val Gln Ala Phe Ala           330                 3 - #35                 3 - #40                 3 -      #45                                                                              - - GTC CTC CCC AAC TCC TCC CTG GCT TCC CTC TT - #C CTG ATT GGC ATG        CAC     1206                                                                    Val Leu Pro Asn Ser Ser Leu Ala Ser Leu Ph - #e Leu Ile Gly Met His                          350  - #               355  - #               360              - - ACA ACT GGT TCC ATG GAG GTC AGC GCC GAG TC - #C AAC AGG CTT GTT GGA         1254                                                                       Thr Thr Gly Ser Met Glu Val Ser Ala Glu Se - #r Asn Arg Leu Val Gly                       365      - #           370      - #           375                  - - GAG CTC AAG CTG GAT AGG CTG CTC CTG GAA CT - #G AAG CAC TCA AAT ATT         1302                                                                       Glu Leu Lys Leu Asp Arg Leu Leu Leu Glu Le - #u Lys His Ser Asn Ile                   380          - #       385          - #       390                      - - GGC CCC TTC CCG GTT GAA TTG CTG CAG GAT AT - #C ATG AAC TAC ATT GTA         1350                                                                       Gly Pro Phe Pro Val Glu Leu Leu Gln Asp Il - #e Met Asn Tyr Ile Val               395              - #   400              - #   405                          - - CCC ATT CTT GTG CTG CCC AGG GTT AAC GAG AA - #A CTA CAG AAA GGC TTC         1398                                                                       Pro Ile Leu Val Leu Pro Arg Val Asn Glu Ly - #s Leu Gln Lys Gly Phe           410                 4 - #15                 4 - #20                 4 -      #25                                                                              - - CCT CTC CCG ACG CCG GCC AGA GTC CAG CTC TA - #C AAC GTA GTG CTT        CAG     1446                                                                    Pro Leu Pro Thr Pro Ala Arg Val Gln Leu Ty - #r Asn Val Val Leu Gln                          430  - #               435  - #               440              - - CCT CAC CAG AAC TTC CTG CTG TTC GGT GCA GA - #C GTT GTC TAT AAA             1491                                                                       Pro His Gln Asn Phe Leu Leu Phe Gly Ala As - #p Val Val Tyr Lys                           445      - #           450      - #           455                  - - TGAAGGCACC AGGGGTGCCG GGGGCTGTCA GCCGCACCTG TTCCTGATGG GC -             #TGTGGGGC   1551                                                                 - - ACCGGCTGCC TTTCCCCAGG GAATCCTCTC CAGATCTTAA CCAAGAGCCC CT -            #TGCAAACT   1611                                                                 - - TCTTCGACTC AGATTCAGAA ATGATCTAAA CACGAGGAAA CATTATTCAT TG -            #GAAAAGTG   1671                                                                 - - CATGGTGTGT ATTTTAGGGA TTATGAGCTT CTTTCAAGGG CTAAGGCTGC AG -            #AGATATTT   1731                                                                 - - CCTCCAGGAA TCGTGTTTCA ATTGTAACCA AGAAATTTCC ATTTGTGCTT CA -            #TGAAAAAA   1791                                                                 - - AACTTCTGGT TTTTTTCATG TG           - #                  - #                   1813                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:252:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 487 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:252:                             - - Met Arg Glu Asn Met Ala Arg Gly Pro Cys As - #n Ala Pro Arg Trp Val     31 -30                - # -25                - # -20                            - - Ser Leu Met Val Leu Val Ala Ile Gly Thr Al - #a Val Thr Ala Ala Val     15                 - - #10                  - #-5                  - # 1        - - Asn Pro Gly Val Val Val Arg Ile Ser Gln Ly - #s Gly Leu Asp Tyr Ala                    5    - #              10    - #              15                  - - Ser Gln Gln Gly Thr Ala Ala Leu Gln Lys Gl - #u Leu Lys Arg Ile Lys               20         - #         25         - #         30                      - - Ile Pro Asp Tyr Ser Asp Ser Phe Lys Ile Ly - #s His Leu Gly Lys Gly           35             - #     40             - #     45                          - - His Tyr Ser Phe Tyr Ser Met Asp Ile Arg Gl - #u Phe Gln Leu Pro Ser       50                 - # 55                 - # 60                 - # 65       - - Ser Gln Ile Ser Met Val Pro Asn Val Gly Le - #u Lys Phe Ser Ile Ser                       70 - #                 75 - #                 80              - - Asn Ala Asn Ile Lys Ile Ser Gly Lys Trp Ly - #s Ala Gln Lys Arg Phe                   85     - #             90     - #             95                  - - Leu Lys Met Ser Gly Asn Phe Asp Leu Ser Il - #e Glu Gly Met Ser Ile               100         - #        105         - #        110                     - - Ser Ala Asp Leu Lys Leu Gly Ser Asn Pro Th - #r Ser Gly Lys Pro Thr          115              - #   120              - #   125                          - - Ile Thr Cys Ser Ser Cys Ser Ser His Ile As - #n Ser Val His Val His      130                 1 - #35                 1 - #40                 1 -      #45                                                                              - - Ile Ser Lys Ser Lys Val Gly Trp Leu Ile Gl - #n Leu Phe His Lys        Lys                                                                                             150  - #               155  - #               160             - - Ile Glu Ser Ala Leu Arg Asn Lys Met Asn Se - #r Gln Val Cys Glu Lys                  165      - #           170      - #           175                  - - Val Thr Asn Ser Val Ser Ser Lys Leu Gln Pr - #o Tyr Phe Gln Thr Leu              180          - #       185          - #       190                      - - Pro Val Met Thr Lys Ile Asp Ser Val Ala Gl - #y Ile Asn Tyr Gly Leu          195              - #   200              - #   205                          - - Val Ala Pro Pro Ala Thr Thr Ala Glu Thr Le - #u Asp Val Gln Met Lys      210                 2 - #15                 2 - #20                 2 -      #25                                                                              - - Gly Glu Phe Tyr Ser Glu Asn His His Asn Pr - #o Pro Pro Phe Ala        Pro                                                                                             230  - #               235  - #               240             - - Pro Val Met Glu Phe Pro Ala Ala His Asp Ar - #g Met Val Tyr Leu Gly                  245      - #           250      - #           255                  - - Leu Ser Asp Tyr Phe Phe Asn Thr Ala Gly Le - #u Val Tyr Gln Glu Ala              260          - #       265          - #       270                      - - Gly Val Leu Lys Met Thr Leu Arg Asp Asp Me - #t Ile Pro Lys Glu         Ser                                                                                 275              - #   280              - #   285                          - - Lys Phe Arg Leu Thr Thr Lys Phe Phe Gly Th - #r Phe Leu Pro Glu        Val                                                                             290                 2 - #95                 3 - #00                 3 -     #05                                                                             - - Ala Lys Lys Phe Pro Asn Met Lys Ile Gln Il - #e His Val Ser Ala Ser                      310  - #               315  - #               320              - - Thr Pro Pro His Leu Ser Val Gln Pro Thr Gl - #y Leu Thr Phe Tyr Pro                  325      - #           330      - #           335                  - - Ala Val Asp Val Gln Ala Phe Ala Val Leu Pr - #o Asn Ser Ser Leu Ala              340          - #       345          - #       350                      - - Ser Leu Phe Leu Ile Gly Met His Thr Thr Gl - #y Ser Met Glu Val Ser          355              - #   360              - #   365                          - - Ala Glu Ser Asn Arg Leu Val Gly Glu Leu Ly - #s Leu Asp Arg Leu Leu      370                 3 - #75                 3 - #80                 3 -      #85                                                                              - - Leu Glu Leu Lys His Ser Asn Ile Gly Pro Ph - #e Pro Val Glu Leu        Leu                                                                                             390  - #               395  - #               400             - - Gln Asp Ile Met Asn Tyr Ile Val Pro Ile Le - #u Val Leu Pro Arg Val                  405      - #           410      - #           415                  - - Asn Glu Lys Leu Gln Lys Gly Phe Pro Leu Pr - #o Thr Pro Ala Arg Val              420          - #       425          - #       430                      - - Gln Leu Tyr Asn Val Val Leu Gln Pro His Gl - #n Asn Phe Leu Leu Phe          435              - #   440              - #   445                          - - Gly Ala Asp Val Val Tyr Lys                                              450                 4 - #55                                                  __________________________________________________________________________

What is claimed is:
 1. An antifungal peptide having from seven to twelveamino acids comprising (a) a core sequence of amino acids selected fromthe group consisting of LIQL, IQLF, WLIQL, LIQLF and WLIQLF; and (b) oneor more cationic amino acids selected from the group consisting of K, R,H ornithine and diaminobutyric acid at the amino and/or carbox terminalportion of the core sequence.
 2. A antifungal peptide having from sevento nine amino acids comprising: (a) a core sequence of amino acidsselected from the group consisting of LIQL and IQLF; and (b) at leasttwo cationic amino acids selected from the group consisting of K, R, H,omnithine and diaminobutyric acid at the amino and/or carboxy terminalportion of the core sequence.
 3. A antifungal peptide having from eightto ten amino acids comprising: (a) a core sequence of amino acidslectedfrom the group consisting of LIQLF and WLIQLF; and (b) at least twocationic amino acids selected from the grouponsisting of K, R, H,ornithine and diaminobutyric acid at the amino and/or carboxy terminalportion of the core sequence.
 4. A antifungal peptide having from nineto twelve amino acids comprising: (a) a core amino acid sequenceselected from the group consisting of WLIQLF; and (b) at least threecationic amino acids selected from the group consisting of K, R, Hornithine and diaminobutyric acid at the amino and/or carboxy terminalportion of the core sequence.
 5. A peptid according to claim 1, 2, 3 or4 having one or more D-isomer amino acids.
 6. A peptid according toclaim 5 wherein said amino acids comprise D-isomer amino acids inreverse sequence order.
 7. A peptide according to claim 1, 2, 3 or 4wherein the amino terminal amino acid residue is acetylated.
 8. A cyclicpeptide according to claim 1, 2, 3 or
 4. 9. A pharmaceutical compositioncomprising a peptide according to any of claims 1 through 8 and apharmaceutically acceptable diluent, adjuvant or carrier.
 10. An invitro method for killing or inhibiting replication of fungi comprisingcontacting the fungi with a peptide according to any one of claims 1through
 8. 11. A method of treating fungal infections comprisingadministering to a subject suffering from a fungal section atherapeutically effective amount of a peptide according to any of claims1 through
 8. 12. A method according to claim 11 wherein the fungalinfection involves a fungal species selected from the group consistingof Candida, Aspergillus and Cryptococcus species.
 13. A method accordingto claim 12 wherein the Candida species is selected from the groupconsisting of C. albicans, C. glabrata, C. krusei, C. lusitaniae, C.parapsilosis and C. tropicalis.
 14. A method according to claim 12wherein the peptide is administered topically, intravenously, orally oras an aerosol.
 15. A method according to claim 12 comprising theadditional step of administering a non-peptide anti-fungal agent.